Abstract: “Transition to psychosis” has been the outcome of interest in Ultra High Risk (UHR) and “prodromal” studies. However, the point at which an individual crosses the line from high risk or prodromal state to psychosis threshold is arbitrary. There have been few attempts to examine whether this threshold has any validity in terms of biological markers or course and outcome. More research is needed to determine if the current point at which a person is declared “psychotic” is valid. Indeed some persons labeled as having developed psychosis may quickly recover. In such a situation their transition could be seen as “trivial”. Others who do not make “transition” may have worse outcomes. Validation of the transition point is an important issue as “risk syndrome for psychosis” (psychosis prodrome) is being considered for inclusion in the DSMV. Further, much research attempts to distinguish markers for psychotic disorders by examining the differences between UHR individuals who do and do not develop psychosis. Thus it behooves us not just to have this risk syndrome validated, but to have the hypothetical endpoint of psychosis validated as well.
Abstract: The proposed Risk Syndrome for Psychosis (RS) criteria are derived from the Ultra High Risk criteria (UHR) and prodromal or Clinical High Risk criteria (CHR), and consist of subthreshold or attenuated positive psychotic symptoms with operationalized recency and frequency criteria. The rationale behind the proposed inclusion of the RS in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSMV) is that several studies have found that the UHR/prodromal/CHR criteria predict onset of psychotic disorder, mainly schizophrenia, within a brief time period of a few years. Identifying individuals meeting these criteria thus affords the possibility of early intervention to prevent or delay onset of full blown psychotic disorder. However, the RS is yet to be properly validated. Additionally, there are potential dangerous unintended consequences of the reification of this syndrome as a formal diagnosis. Thus we feel it is premature to justify inclusion of the RS in the DSM.
Abstract: The inclusion of a psychosis risk syndrome has been proposed for the 5th edition of the Diagnostic and Statistical Manual of Mental Disorders. The appropriateness of inclusion of this new risk syndrome in the DSM depends on a careful analysis of both anticipated benefits and risks. Purported benefits include early recognition and case identification, and the hypothetical benefit of preventive intervention of psychotic disorders, for which there is as yet no clear evidence base. However, there is a potential for high rates of false positives particularly at the community level given the difficulty in discriminating mild symptoms from normal variants and low base rates of the syndrome in the general population. High false-positive rates in and of themselves are not necessarily problematic if the risk–benefit ratio is significantly favorable, as with screening for cardiovascular risk factors. For the psychosis risk syndrome, by contrast, there are substantial risks, for both stigma and discrimination, and for unnecessary exposure to antipsychotic medications, which make the high false-positive rate associated with the psychosis risk designation particularly problematic. More research is needed to improve the positive predictive value of the psychosis risk syndrome so that it can be considered for inclusion in future editions of the DSM.
Abstract: Current criteria for an increased risk of developing first-episode psychosis are associated with conversion rates many times higher than the general incidence of psychosis. Yet, non-conversions still outnumber conversions, and conversion rates across and within centres vary considerably, fueling the ongoing debate about clinical and ethical justification of indicated prevention. This debate, however, almost exclusively focuses on the predictive validity of at-risk criteria, thereby widely disregarding the main general finding: persons meeting at-risk criteria already suffer from multiple mental and functional disturbances for those they seek help. Moreover, they exhibit various psychological and cognitive deficits along with morphological and functional cerebral changes. Thereby, the majority of help-seeking at-risk persons fulfils DSM-IV’s general criteria for mental disorders (defined as a clinically significant behavioural or psychological syndrome associated with disability and/or severe distress) and clearly have to be considered as ‘ill’, i.e., as ‘patients’ with a need and right for treatment.Hence, the clinical picture defined by current at-risk criteria should be more adequately perceived as not only a still insufficient attempt to define the psychotic prodrome but a psychosis spectrum disorder in its own right – akin to ICD-10’s schizotypal disorder – with conversion to psychosis just being one of several outcomes. Such a disorder, whose criteria are proposed and discussed, should initially be part of DSM-V research criteria. Following from this shift in the perception of current at-risk criteria, access to standard medical care would have to be granted, and diagnosis- or symptom- rather than conversion-related interventions would have to be developed.
There is now a proposal to include a “risk syndrome for first psychosis” in DSM V (). To summarize the criteria: at least one of delusions, hallucinations or disorganized speech must be present, sufficiently attenuated to preserve reality testing and not to substantially interfere with thinking or behaviour. However, they must be distressing and be associated with decrements in social, cognitive or vocational function. The symptoms must have occurred at least weekly, on average, in the past month and worsened or begun in the past year. Other DSM V diagnoses must not better explain them and psychosis must never have occurred.
Abstract: While the “clinical high-risk state” for psychosis has demonstrated good reliability and fair predictive validity for psychotic disorders, over 50% of identified subjects do not progress to psychosis. Despite the benefits that early detection and treatment might offer, debate concerning the official inclusion of a “psychosis risk syndrome” in the upcoming DSM-V frequently involves concerns about the impact of stigma on patients, families and institutions. We add to this debate by providing an analysis of the theoretical and empirical stigma literature to evaluate the potential effects of stigma associated with the psychosis risk syndrome. Theorists’ conceptualizations of how stigma exerts its negative effects emphasize internalization of pejorative societal stereotypes (‘self-stigma’), negative emotional reactions, harmful behavioral coping strategies, and structural discrimination as key mechanisms. Studies assessing the comparative effects of symptomatic behavior when compared with a psychiatric diagnosis label in predicting rejecting social attitudes indicate that treating symptomatic behaviors is likely to diminish overall stigma. However, any publically held ‘preexisting conceptions’ about what a psychosis risk syndrome means are still likely to exert negative effects. Additionally, particular features of this syndrome—that it occurs during adolescence when identity formation may be in flux— may also shape manifestations of stigma. Utilizing other well-established ‘at-risk’ conditions (e.g., genetic susceptibility) to model potential discrimination for this syndrome, we suggest that future discrimination is likely to occur in insurance and family domains. We conclude by proposing stigma measurement strategies, including recommending that field trials prior to DSM-V adopt systematic measures to assess any stigma that this psychosis risk syndrome might confer via future community use.
The proposal to consider including the concept of the risk syndrome in the forthcoming revision of the DSM classification is innovative and timely. It has not come out of left field, however, and is based upon a series of conceptual and empirical foundations built over the past 15years. Since the term “risk” is central to the proposal, let us initially consider the notion of risk and risk factors.
Abstract: Background: Lateral ventricular enlargement is one of the most consistent findings in patients with schizophrenia; however whether progressive ventricular dilation occurs during the course of the illness has been controversial. To clarify this we conducted a meta-analysis of longitudinal studies measuring the lateral ventricles in patients with schizophrenia and a control group.Methods: The MEDLINE database was searched from 1980 to 2009 for longitudinal MRI studies of patients with schizophrenia. We identified 13 studies that measured the lateral ventricles in both patients and controls and these were included in a random effects meta-analysis. The effect of various clinical variables was investigated in a meta-regression analysis.Results: Patients showed evidence of progressive ventricular enlargement after illness onset greater than that seen in controls (effect size=0.45, 95%CI 0.19–0.71, p=0.0006). A sub-analysis of chronic patients with schizophrenia with a mean duration of illness of 7.6years at baseline scan also showed progressive ventricular enlargement (p=0.002). The results were robust to inclusion criteria, and no significant effect of age of onset, duration of illness, or age at baseline scan, was found in the meta-regression analysis.Conclusions: The meta-analysis shows progressive changes in ventricular volume a number of years after illness onset and challenges an exclusively neurodevelopmental model of schizophrenia.
Abstract: Deficit schizophrenia (D-SZ) has been proposed as a putative disease subtype defined by prominent, primary negative symptoms that endure as trait-like features during periods of clinical stability. In this study, we acquired magnetic resonance images of the whole brain using a 1.5T scanner in 19 outpatients with D-SZ, 31 with non-deficit schizophrenia (ND-SZ), and 90 healthy adults. Voxel-based morphometry was used to investigate differences in regional gray-matter volume (GMV) between outpatients with D-SZ and ND-SZ, and between the combined patient subgroups and healthy adults. Compared to healthy adults outpatients with schizophrenia showed GMV reductions, especially in left frontal and temporal cortices and in the left insula. The D-SZ subgroup showed reduced GMV in the insula bilaterally and in the left superior frontal, middle temporal and occipital gyri. Regions in which GMV reductions best distinguished D-SZ from ND-SZ patients included the superior frontal gyrus (Brodmann area 
and superior temporal gyrus (Brodmann areas 22, 38) bilaterally, the left supplementary motor area (Brodmann area 6), left anterior cingulate, left cuneus and right putamen. These results suggest that patients with deficit schizophrenia have brain abnormalities that differ from those of patients with non-deficit schizophrenia. Further, the neuroanatomic differences between these two putative subtypes of schizophrenia involve brain regions that appear to be associated with the negative symptoms that define the deficit syndrome of schizophrenia.
Abstract: Background: Patients with schizophrenia commonly show deficits in working memory on objective neuropsychological measures, and brain imaging studies have documented neural abnormalities during performance of working memory tasks. It remains unclear to what extent such patients are able to accurately gauge the integrity of their working memory in their daily lives.Aims: We evaluated the relationship between subjective rating of working memory integrity in daily life and volumes of the frontal, temporal, and parietal lobes in patients with schizophrenia.Methods: Participants included 29 patients with schizophrenia and 26 healthy comparison subjects. Participants completed a structural magnetic resonance imaging (MRI) scan, the Self Report form of the Behavioral Rating Inventory of Executive Function — Adult version (BRIEF-A), and Digit Span Backwards as an objective measure of working memory. Lobar volumes were obtained using an automated processing package and adjusted for total intracranial volume.Results: The patient group reported worse working memory in daily life, and performed worse on Digit Span Backwards, than the comparison group. Within the patient group, poorer working memory in daily life was associated with smaller left and right frontal lobe volumes. Shorter backwards digit span was associated with smaller left frontal and left and right temporal lobe volumes.Conclusions: The significant relationship between frontal lobe volumes and subjective working memory in daily life provides some support for the validity of self report measures of cognitive functioning in patients with schizophrenia, and provides further evidence for a contribution of frontal lobe abnormality to executive dysfunction in the illness.
Abstract: Previous work has demonstrated less accurate alignment of cortical structures for patients with schizophrenia than for matched control subjects when using affine registration techniques. Such a mismatch presents a potential confound for functional neuroimaging studies conducting between-group comparisons. Critically, the same issues may be present for subcortical structures. However, to date no study has explicitly investigated alignment precision for major subcortical structures in patients with schizophrenia. Thus, to address this question we used methods previously validated for assessment of cortical alignment precision to examine alignment precision of subcortical structures. In contrasts to our results with cortex, we found that major subcortical structures (i.e. amygdala, caudate, hippocampus, pallidum, putamen and thalamus) showed similar alignment precision for schizophrenia (N=48) and control subjects (N=45) regardless of the template used (other individuals with schizophrenia or healthy controls). Taken together, the present results show that, unlike cortex, alignment for six major subcortical structures is not compromised in patients with schizophrenia and as such is unlikely to confound between-group functional neuroimaging investigations.
Abstract: Meta-analyses in adult-onset schizophrenia report loss of normal planum temporale (PT) asymmetry, posited to relate to language and symptoms, but are inconclusive regarding global “cerebral torque”. PT asymmetry has been reported unchanged in childhood onset schizophrenia. Here the discrepancy is examined in adolescence. Unbiased PT asymmetry and torque measures were obtained on 35 adolescents with schizophrenia or schizoaffective disorder and 31 adolescent controls. Patients had less PT asymmetry than controls, but torque was unchanged. Taken with previous reports, these results in adolescent onset psychosis suggest that local disturbance of cerebral asymmetry increases with patient age; it could indicate that differential rate of change at the cortical surface in the two hemispheres is the mechanism of symptom generation.
Abstract: Objectives: The aims of this study were to estimate the frequency and course of substances use disorders in Latino patients with schizophrenia and to ascertain risk factors associated with substance use disorders in this population.Method: We studied 518 subjects with schizophrenia recruited for a genetic study from the Southwest United States, Mexico, and Central America (Costa Rica and Guatemala). Subjects were assessed using structured interviews and a best estimate consensus process. Logistic regression, χ2, t test, Fisher’s exact test, and Yates’ correction, as appropriate, were performed to assess the sociodemographic variables associated with dual diagnosis. We defined substance use disorder as either alcohol or substance abuse or dependence.Results: Out of 518 patients with schizophrenia, 121 (23.4%) had substance use disorders. Comorbid substance use disorders were associated with male gender, residence in the United States, immigration of Mexican men to the United States, history of depressive syndrome or episode, and being unemployed. The most frequent substance use disorder was alcohol abuse/dependence, followed by marijuana abuse/dependence, and solvent abuse/dependence.Conclusion: This study provides data suggesting that depressive episode or syndrome, unemployment, male gender, and immigration of Mexican men to the United States were factors associated with substance use disorder comorbidity in schizophrenia. Binary logistic regression showed that country of residence was associated with substance use disorder in schizophrenic patients. The percentage of subjects with comorbid substance use disorders was higher in the Latinos living in the United States compared with subjects living in Central America and Mexico.
Abstract: Objective: Despite the controversy surrounding the possible causal link between cannabis use and the onset of schizophrenia (SZ), data seeking to elucidate the effect of cannabis use disorders (CUDs) on the clinical presentation of SZ have produced mixed results. Although several studies have suggested that CUD in patients with SZ may be associated with variation in cognitive function, clinical presentation and course of illness, the effects have been inconsistent.Methods: We retrospectively ascertained a large cohort (N=455) of SZ patients with either no history of a CUD (CUD−; N=280) or a history of CUD (CUD+; N=175). The groups were initially compared on key demographic variables including sex, race, age, age at onset of SZ, parental socioeconomic status, premorbid IQ, education level and global assessment of functioning. Covarying for any observed differences in demographic variables, we then compared groups on lifetime measures of psychotic symptoms as well as a brief battery of neurocognitive tests.Results: Compared to the CUD− group the CUD+ group demonstrated significantly better performance on measures of processing speed (Trail Making Tests A and B), verbal fluency (animal naming) and verbal learning and memory (California Verbal Learning Test). Moreover, the CUD+ group had better GAF scores than the CUD group.Conclusions: Collectively, these findings suggest that SZ patients with comorbid CUD may represent a higher functioning subgroup of SZ. Future prospective studies are needed to elucidate the nature of this relationship.
Abstract: Introduction: The purpose of this study is to determine if an earlier age at onset of positive symptoms in schizophrenia is associated with cannabis use disorders (CUD).Methods: 49 first-episode schizophrenia subjects with CUD were compared to 51 first-episode schizophrenia subjects with no substance use disorders for demographic and clinical variables. A multivariate logistic regression was performed to determine the joint relationship between variables significantly associated with CUD on univariate testing and ascertain if these variables independently predict CUD. Significance level was set at p<0.05.Results: 74% of CUD subjects had the onset of CUD before the onset of positive symptoms. Compared to non-substance abusing subjects, CUD subjects were predominantly male, younger at study entry, had an earlier age at onset of positive symptoms, less educational attainment, a lower self-socioeconomic status, better premorbid childhood social adjustment, a trend for poorer premorbid childhood academic adjustment, less motor abnormalities but more severe hallucinations and delusions. In the multivariate analysis, only male gender, worse socio-economic status, better premorbid childhood social adjustment, and more severe positive symptoms at study entry were associated with a lifetime history of CUD.Discussion: Although cannabis use precedes the onset of illness in most patients, there was no significant association between onset of illness and CUD that was not accounted for by demographic and clinical variables. Previous studies implicating CUD in the onset of schizophrenia may need to more comprehensively assess the relationship between CUD and schizophrenia, and take into account additional variables that we found associated with CUD.
Abstract: Background: Consanguinity has been suggested as a risk factor for psychoses in some Middle Eastern countries, but adequate control data are unavailable. Our recent studies in Egypt have shown elevated parental consanguinity rates among patients with bipolar I disorder (BP1), compared with controls. We have now extended our analyses to schizophrenia (SZ) in the same population.Methods: A case–control study was conducted at Mansoura University Hospital, Mansoura, Egypt (SZ, n=75; controls, n=126, and their available parents). The prevalence of consanguinity was estimated from family history data (‘self report’), followed by DNA analysis using short tandem repeat polymorphisms (STRPs, n=63) (‘DNA-based’ rates).Results: Self-reported consanguinity was significantly elevated among the patients (SZ: 46.6%, controls: 19.8%, OR 3.53, 95% CI 1.88, 6.64; p=0.000058, 1 d.f.). These differences were confirmed using DNA-based estimates for coefficients of inbreeding (inbreeding coefficients as means±standard error, cases: 0.058±0.007, controls: 0.022±0.003).Conclusions: Consanguinity rates are signifcantly elevated among Egyptian SZ patients in the Nile delta region. The associations are similar to those observed with BP1 in our earlier study. If replicated, the substantial risk associated with consanguinity raises public health concerns. They may also pave the way for gene mapping studies.
Abstract: Whether avoidant personality disorder symptoms are related to neurocognitive impairments that aggregate in relatives of schizophrenics is unknown. We report the relationship between avoidant personality disorder symptoms and neurocognitive performance in the first-degree relatives of probands with schizophrenia.367 first-degree relatives of probands with schizophrenia and 245 relatives of community controls were interviewed for the presence of avoidant personality symptoms and symptoms of paranoid and schizotypal personality disorders and administered neurocognitive measures. Relationships between neurocognitive measures and avoidant symptoms were analyzed using linear mixed models.Avoidant dimensional scores predicted performance on the span of apprehension (SPAN), 3–7 Continuous Performance Test (3–7 CPT), and Trail Making Test (TMT-B) in schizophrenia relatives. These relationships remained significant on the SPAN even after adjustment for paranoid or schizotypal dimensional scores and on the TMT-B after adjustment for paranoid dimensional scores. Moreover, in a second set of analyses comparing schizophrenia relatives to controls there were significant or trending differences in the degree of the relationship between avoidant symptoms and each of these neurocognitive measures even after adjustments for paranoid and schizotypal dimensional scores. The substantial correlation between avoidant and schizotypal symptoms suggests that these personality disorders are not independent.Avoidant and in some cases schizotypal dimensional scores are significant predictors of variability in these neurocognitive measures. In all analyses, higher levels of avoidant symptoms were associated with worse performance on the neurocognitive measures in relatives of schizophrenia probands. These results support the hypothesis that avoidant personality disorder may be a schizophrenia spectrum phenotype.
Abstract: The results of research on the relation of family history (FH) of psychosis with clinical presentation in schizophrenia have been mixed. To date, there have been no comprehensive reviews that have examined this body of research. The current review quantitatively evaluates research on the relation of FH with two aspects of schizophrenia, age-at-onset and symptom presentation. Studies investigating the influence of a FH on age-at-onset (N=15 studies), age-at-onset and sex (N=12 studies), and/or positive (N=11 studies) and negative symptoms (N=12 studies) in patients with schizophrenia were included in the meta-analyses. Results showed that FH has a small but significant impact on age-at-onset as well as negative symptoms. Of most interest was the finding that sex differences in age-at-onset are not observed in samples with a FH. Furthermore, there was a significant interaction between FH and sex with respect to negative symptoms. The findings of the current review are discussed in light of the diathesis-stress model. Theoretical assumptions and empirical research are reviewed to support the notion that FH influences susceptibility and presentation through similar mechanisms. Implications of the current findings, limitations of the review, and directions for future research are highlighted.
Abstract: Recent genetic studies have revealed that the Interleukin-1 (IL1) gene complex (IL1 alpha, IL1 beta and IL1 receptor antagonist) is associated with schizophrenia, but contradictory findings have also been reported. We investigated the association of the IL1 gene complex locus and schizophrenia using meta-analytic techniques, covering all published data up to January 2010, to restrict to the most commonly reported 4 single nucleotide polymorphisms (SNP). We also explored potential sources of heterogeneity and to investigate whether ancestry and study design moderated any association. The combined allele-wise odds ratio (OR) for schizophrenia of the rs16944 (IL1B gene; T-511C) polymorphism was 0.86 (95% CI: 0.77to 0.96).When applying stratified analysis to this polymorphism, the pooled allele-wise OR was 0.88 (95% CI, 0.79 to 0.97) in 10 population-based studies and 0.85 (95% CI: 0.73 to 0.99) in Caucasian samples. In a stratified analysis of the rs1143634 (IL1B gene; T3953C) polymorphism, the pooled genotype-wise results in a dominant model were also statistically significant both in a population-based study subgroup with summary OR of 0.64 (95% CI: 0.41 to 0.99) and a Caucasian population subgroup with summary OR of 0.62 (95% CI: 0.40 to 0.97). Neither combined nor stratified analyses found any association of the rs1800587 (IL1A gene; T-889C) or rs1794068 (IL1RA Gene; IL1RN_86 bp; T/C) with schizophrenia susceptibility. Our study suggests the IL1B gene or the IL1 gene complex may play a moderate role in the etiology of schizophrenia in the Caucasian population.
Abstract: Background: We previously identified the neuronal PAS3 (NPAS3) gene as a candidate gene for schizophrenia. A mother and daughter, both with schizophrenia, were carriers of a translocation, t(9;14)(q34;q13), that disrupts the NPAS3 gene. The gene is located at 14q13, a region implicated in schizophrenia and bipolar disorder in various linkage studies. NPAS3 belongs to the basic helix-loop-helix Per-Arnt-Sim (bHLH-PAS) transcription factor family, involved in diverse processes including the regulation of cell differentiation and circadian rhythms, and the development and function of the nervous system.Methods: The 12 exons encoding NPAS3 were sequenced in DNA from individuals with schizophrenia. NPAS3 variants were identified in exons 6 and 12, initially in 12 patients only. These two exons were then sequenced in 83 patients and 83 controls.Results and conclusion: Three common variants of NPAS3, also found in controls, showed a positive association with schizophrenia (NM_001164749: rs12434716, c.1654G>C, p=0.009; rs10141940, c.2208C>T, p=0.01; rs10142034, c.2262C>G, p=0.01). The c.1654G>C variant, results in an p.Ala552Pro change and may affect NPAS3 protein function directly. Alternatively, the three SNPs may affect the splicing of NPAS3 transcripts, as they are each located within putative exonic splicing enhancer (ESE) motifs (ESEFinder). A c.726C>T variant, identified in three patients, is located in an ESE element and is predicted to reduce the function of the motif. Other variants, identified in controls, included c.2089G>A (p.Gly697Ser) and c.2097T>C. Our identification of potentially defective NPAS3 variants supports recent studies that implicate perturbations in NPAS3 pathways in impaired neurogenesis and psychosis.
Abstract: Deficits in the expression of oligodendrocyte (Ol) and myelin genes have been described in numerous brain regions in schizophrenia (SZ) in association with abnormalities of cell cycle markers. We have previously reported a SZ-associated decrease in the expression of genes expressed after, but not prior to, the terminal differentiation of Ols in the posterior limb of the internal capsule (ICp). This pattern of deficits could reflect a failure of Ol precursors to exit the cell cycle and differentiate to meet the demands imposed by the high rate of apoptosis among myelinating Ols. Here we explore this hypothesis using quantitative real time PCR to examine the mRNA expression of additional genes in the ICp of the previously examined sample of 14 subjects with SZ and 15 normal controls (NCs). The genes examined in the present study were chosen because they are associated with particular phases of the cell cycle (CCND1, CCND2, p21Cip1, p27Kip1, and p57Kip2), with DNA replication and repair (PCNA), apoptosis (CASP3), or the Notch signaling pathway (JAG1, HES1, HES5, and DTX1). The Notch pathway influences whether Ol precursors continue to proliferate or exit the cell cycle. We also determined the densities of Ols in the ICp. Genes associated with maintenance of the cell cycle tended to exhibit increased expression levels in SZ relative to NCs and to be negatively correlated with the expression levels of the previously assessed mature Ol genes. In contrast, genes associated with cell cycle arrest tended to show the opposite pattern (decreased expression in SZ and positive correlations with mature Ol genes). CASP3 and PCNA expression levels were significantly decreased in SZ and positively correlated with mature Ol genes, suggesting that myelinating Ols may turnover more rapidly in normal controls than in subjects with SZ. JAG1 expression was significantly increased in SZ and exhibited positive correlations with mediators of the canonical Notch pathway but negative correlations with mature Ol genes. Ol densities were significantly decreased in SZ. These data are consistent with the hypothesis that Ol and myelin deficits in SZ involve a failure of Ol precursors to appropriately exit the cell cycle in order to differentiate and mature into myelinating Ols.
Abstract: Association with schizophrenia of the Abelson Helper Integration Site 1 (AHI1) gene on chromosome 6q23 and the adjacent primate-specific gene, C6orf217, was demonstrated in an inbred, Arab Israeli family sample and replicated in an Icelandic case control sample. Further support was provided by a second replication in a large European sample and a meta-analysis that supported association with schizophrenia of all seven alleles overtransmitted to affected subjects in the original study. We examined constitutive expression of AHI1 and C6orf217 in immortalized lymphoblasts of patients from the Arab Israeli family sample in which the association with schizophrenia was originally discovered and population-matched normal controls, and in post-mortem brain of patients with schizophrenia and bipolar (BP) disorder and control subjects from the Stanley Medical Research Institute Collection. We found a significant effect of diagnostic group in the lymphoblast sample (F=5.72; df=2,39; p=0.006). Patients with early age of onset had higher AHI1 expression than controls and later onset patients (p=0.002; 0.03 respectively). C6orf217 expression in lymphoblasts was too low to measure. We found no difference in brain expression of AHI1 in schizophrenia or BP patients compared to controls. However, there was a genotypic difference in AHI1 expression for SNP rs9321501, which was strongly associated with schizophrenia in the original study. Genotypes that included the undertransmitted C allele (CC/AC) showed lower expression than the homozygous AA genotype (F=4.73, df=2,83; p=0.028). There was no significant difference in brain expression of C6orf217 between patients and controls and no genotypic effect. This study provides further evidence for involvement of AHI1 in susceptibility to schizophrenia.
Abstract: Subtle emotional and cognitive dysfunctions may already be apparent in individuals at risk for psychosis. However, there is a paucity of research on the neural correlates of the interaction of both domains. It remains unclear whether those correlates are already dysfunctional before a transition to psychosis.We used functional magnetic resonance imaging to examine the interaction of working memory and emotion in 12 persons clinically at high risk for psychosis (CHR) and 12 healthy subjects individually matched for age, gender and parental education. Participants performed an n-back task while negative or neutral emotion was induced by olfactory stimulation.Although healthy and psychosis-prone subjects did not differ in their working memory performance or the evaluation of the induced emotion, decreased activations were found in CHR subjects in the superior parietal lobe and the precuneus during working memory and in the insula during emotion induction. Looking at the interaction, CHR subjects, showed decreased activation in the right superior temporal gyrus, which correlated negatively with psychopathological scores. Decreased activation was also found in the thalamus. However, an increase of activation emerged in several cerebellar regions.Dysfunctions in areas associated with controlling whether incoming information is linked to emotional content and in the integration of multimodal information might lead to compensatory activations of cerebellar regions known to be involved in olfactory and working memory processes. Our study underlines that cerebral dysfunctions related to cognitive and emotional processes, as well as their interaction, can emerge in persons with CHR, even in absence of behavioral differences.
Abstract: Background: It is unclear to what extent non-clinical psychotic experiences during childhood and adolescence share underlying aetiological mechanisms with schizophrenia. One candidate mechanism for schizophrenia involves the epigenetic status of the developing fetus, which depends on the internal folate-status of mother and child. Our study examines the relationships between multiple determinants of perinatal folate-status and development of psychotic experiences in adolescence.Methods: Study participants were up to 5344 mother–child pairs from the Avon Longitudinal Study of Parents and their Children, UK, with information on maternal and/or child MTHFR C677T genotype, maternal folate intake (supplementation at 18/32- weeks gestation; dietary intake at 32- weeks gestation) and psychosis-like symptoms (PLIKS) for children assessed at age 12.Results: Nominal evidence was observed that maternal folate supplementation at 18weeks increased the odds of PLIKS in children (odds ratio(OR)=1.34; 95%-CI:[1.00;1.76]) and, consistent with this, that children of MTHFR C667T TT homozygous mothers had decreased odds of PLIKS (OR=0.72; 95%CI:[0.50;1.02]; recessive model) with strongest effects in boys (OR=0.44, 95%-CI:[0.22;0.79]; sex-specific p=0.029). None of the reported effects remained significant when corrected for multiple testing.Conclusions: Overall, this study found no support that maternal/child MTHFR C677T genotype and maternal folate intake during pregnancy contribute to common aetiological pathways that are shared between schizophrenia and non-clinical psychotic symptoms in adolescents, assuming that decreased folate-status increases schizophrenia risk.
Abstract: Background: The presence of a psychosis continuum is suggested by studies showing that schizophrenia and non-clinical psychotic symptoms in the general population share the same risk factors. However, to our knowledge no large-scale studies have been conducted which examine the specificity of these risk factors in the general population.Aim: To investigate whether socio-demographic characteristics associated with non-clinical psychotic symptoms are also associated with other psychiatric symptoms. And secondly, to examine to what extent concomitant psychiatric symptoms explain the relationship between socio-demographic characteristics and non-clinical psychotic symptoms.Methods: In a general population sample of 4894 subjects (mean age 39years, 45% men) from the Utrecht Health Project we investigated the associations of socio-demographical characteristics with non-clinical psychotic symptoms and other psychiatric symptoms by using the SCL-90. We examined these associations using multivariable logistic regression analyses with and without controlling for the presence of other psychiatric symptoms.Results: Participants with non-clinical psychotic symptoms had an 89% probability of concomitant depressive, anxiety or phobic anxiety symptoms, compared to 11% in participants without psychotic symptoms. The risk profiles for non-clinical psychotic symptoms and other psychiatric symptoms were largely similar. Non-Dutch ethnicity was most strongly associated with non-clinical psychotic symptoms. Adjusting for other psychiatric symptoms did not increase the specificity of the risk factors.Conclusion: Socio-demographic risk factors for non-clinical psychotic symptoms in the general population are also risk factors for other psychiatric symptoms. The relationship between these risk factors and psychotic symptoms are for a substantial part explained by an increase in other psychiatric symptoms.
Abstract: Background: Cognitive deficits are a core feature in schizophrenia. Cognitive deficits appear to be present at the onset of schizophrenia and persist after remission of psychotic symptoms. As cognitive deficits are associated with poor functional outcome, they form an important focus of treatment. There are relatively few head-to-head comparisons of the effects of second generation antipsychotics on cognition in recent onset schizophrenia. This is the first study to compare the effects of a short term treatment of olanzapine versus ziprasidone on cognitive functioning in recent onset schizophrenia. An earlier study conducted in chronic patients revealed an enhancement of cognition after treatment for both agents, but the extent of improvement was not significantly different between ziprasidone and olanzapine.Method: Patients with recent onset schizophrenia with limited previous exposure to medical treatment underwent a double blind randomized controlled treatment trial. Fifty-six patients completed the neuropsychological testing procedure prior to randomization and after eight weeks of treatment and were included in the analysis. We tested cognitive functioning in general and verbal memory in particular. We calculated a single unweighted composite score based on nine cognitive tests to determine general cognitive functioning.Results: Cognition appeared enhanced after treatment, but was not significantly different between treatment groups, neither for the verbal memory measures, nor for the neurocognitive composite score. Furthermore, cognitive enhancement did not correlate to clinical improvement.Conclusion: Cognitive deficits are not a reason for preferentially prescribing one of the two second generation antipsychotics tested over the other.
Abstract: Background and aim: Improving social functioning is critically important in early-episode schizophrenia, if patients are to achieve functional recovery. This post-hoc, pooled analysis of two studies compared the effect of aripiprazole versus haloperidol on social functioning in early-episode schizophrenia.Methods: Data were pooled from two 52week, randomized (2:1), double-blind, multicenter studies involving 1294 patients with chronic schizophrenia who were in an acute psychotic episode and had a history of positive antipsychotic response during previous episodes. The early-episode group was defined as patients who are ≤40years of age with ≤5years’ duration of illness. Social functioning was assessed by mean change from baseline on the PANSS Prosocial subscale (ANCOVA and LOCF), comprising six PANSS items, and the Modified Prosocial subscale, comprising four PANSS items. Measurements were taken at approximately monthly intervals for up to 1year.Results: Aripiprazole (n=237) demonstrated significant improvement versus haloperidol (n=123) as early as Week 18 on both the Prosocial subscale (−4.75 versus −3.78, p<0.05) and on the Modified Prosocial subscale (−3.16 versus −2.28, p<0.05). Patients receiving aripiprazole continued to show similar significant improvement versus haloperidol at all remaining timepoints through Week 52 using the Modified Prosocial subscale, but less consistent improvement with the Prosocial subscale. Significant advantage for the aripiprazole-treated patients was observed at Weeks 46 and 52 (endpoint) with both subscales.Conclusion: In patients with early-episode schizophrenia, aripiprazole demonstrates greater improvement than haloperidol on PANSS items related to social functioning. The cognitive and functional implications of these findings remain to be clarified in future studies.
Abstract: Objective: Metabolic syndrome and elevated lipids, related to cardiovascular risk factors, are more prevalent in schizophrenia and there has been much debate about the extent to which specific antipsychotics contribute more to the increased risk of developing hyperlipidemia and metabolic syndrome. Most studies have concentrated on fasting levels in patients recently started on medication. Randomized prospective studies of metabolic effects of 2nd generation antipsychotics using both fasting measures and provocative tests may provide results that are more informative. We present results of a randomized prospective study of lipid metabolism and metabolic syndrome in chronic schizophrenic patients using both fasting and post-prandial lipid measures.Method: Hospitalized patients with chronic schizophrenia, most of whom had been treated with multiple antipsychotics in the past, were randomly assigned to treatment with a single antipsychotic, olanzapine or risperidone, for a period of 5months. At baseline and every treatment month thereafter, fasting levels of lipids, free fatty acid (FFA) and leptin were assessed. At baseline and end of month 2 of treatment patients had a fatty meal test (FMT) in which postprandial lipids were measured at several time points before and after meal ingestion. Weight was assessed monthly and waist measures were taken at baseline and month 5. Data was analyzed on 23 patients randomized to risperidone and 23 patients randomized to olanzapine.Results: Overall, there were no differential drug effects on any fasting lipid measure and fasting triglycerides did not increase in olanzapine treated patients after 5months of treatment. However, at 2months of drug treatment the FMT revealed a significantly greater increase in triglycerides, and very low density (VLDL) cholesterol and triglycerides, in olanzapine compared to risperidone patients (Ps=.05–.01). There was no difference between treatments with olanzapine vs. risperidone on development of metabolic syndrome during the 5month treatment period.Conclusions: Chronic schizophrenic patients treated for years with first and second generation antipsychotics may have developed tolerance to the effects of olanzapine on increasing fasting triglycerides and other lipids, but some underlying metabolic abnormalities may be revealed in postprandial tests of lipid metabolism. These findings suggest that the development of standardized tests and criteria for measurement of postprandial triglycerides and related lipid levels, in addition to fasting levels, may be helpful in identifying metabolic effects of olanzapine and other second generation antipsychotics in chronically treated schizophrenics. In some reports postprandial increases in triglycerides have been identified as important risk factors for cardiovascular disease, but the actual differential consequences of these lipid metabolic differences for development of atherosclerosis and cardiovascular disease in patients treated with different antipsychotics need more objective outcome measures to determine and quantify cardiovascular risk outcomes.
Abstract: Cognitive rehabilitation is an effective intervention for addressing cognitive impairments in patients with schizophrenia. Previous research has shown that the early application of Cognitive Enhancement Therapy (CET) can improve neurocognitive and social-cognitive deficits in the early course of the disorder, and ultimately reduce the substantial functional disability that these patients experience. However, the lasting effects of CET on functional outcome in early course schizophrenia patients remain unknown. In this study, 58 patients in the early course of schizophrenia or schizoaffective disorder treated with 2years of either CET or an Enriched Supportive Therapy (EST) control were followed-up 1year after the completion of treatment to examine the durability of CET effects on functional outcome. At one-year post-treatment, a high (72%) retention rate was observed in both treatments. Results from intent-to-treat analyses employing linear mixed-effects models indicated that CET effects on functional outcome were broadly maintained one-year post-treatment, and that patients receiving CET continued to demonstrate highly significant differential functional benefits compared to patients treated with EST. These findings support the durability of CET effects on functional outcome in the early course of schizophrenia, and point to the potential of cognitive rehabilitation to have a lasting impact on the early trajectory of the disorder.
