Schizophrenia Research

Editorial Board

2013-06-01

Human brain imaging studies of DISC1 in schizophrenia, bipolar disorder and depression: A systematic review

2013-04-18

Abstract: Disrupted-in-Schizophrenia 1 (DISC1) is a well researched candidate gene for schizophrenia and affective disorders with a range of functions relating to neurodevelopment. Several human brain imaging studies investigating correlations between common and rare variants in DISC1 and brain structure and function have shown conflicting results. A meta-analysis of case/control data showed no association between schizophrenia and any common SNP in DISC1. Therefore it is timely to review the literature to plan the direction of future studies.Twenty-two human brain imaging studies have examined the influence of DISC1 variants in health, schizophrenia, bipolar disorder or depression. The most studied common SNPs are Ser704Cys (rs821616) and Leu607Phe (rs6675281). Some imaging-genomic studies report effects on frontal, temporal and hippocampal structural indices in health and illness and a volumetric longitudinal study supports a putative role for these common SNPs in neurodevelopment. Callosal agenesis is described in association with rare deletions at 1q42 which include DISC1 and rare sequence variants at DISC1 itself. DISC1 interactions with translin-associated factor X (TRAX) and neuregulin have been shown to influence several regional volumes. In the first study involving neonates, a role for Ser704Cys (rs821616) has been highlighted in prenatal brain development with large clusters of reduced grey matter reported in the frontal lobes.Functional MRI studies examining associations between Ser704Cys (rs821616) and Leu607Phe (rs6675281) with prefrontal and hippocampal activation have also given inconsistent results. Prefrontal function was reported to be associated with interaction between DISC1 and CITRON (CIT) in health. Preliminary magnetic resonance spectroscopy and diffusion tensor data support the influence of Ser704Cys (rs821616) status on grey and white matter integrity. The glutamate system remains uninvestigated.Associations between rare sequence variants and structural changes in brain regions including the corpus callosum and effects of gene–gene interactions on brain structure and function are promising areas for future study.

Paliperidone protects prefrontal cortical neurons from damages caused by MK-801 via Akt1/GSK3β signaling pathway

2013-04-11

Abstract: Recent studies have suggested that neurodegeneration is involved in the pathogenesis of schizophrenia, and some atypical antipsychotics appear to prevent or retard progressive morphological brain changes. However, the underlying molecular mechanisms are largely unknown. Whether changes in intracellular signaling pathways are related to their neuroprotective effects remains undefined. In the present study, we used mouse embryonic prefrontal cortical neurons to examine the neuroprotection of paliperidone against the neuronal damage induced by exposure to the NMDA receptor antagonist, MK-801. Paliperidone inhibited MK-801 induced neurotoxicity both in MTT metabolism assay (p<0.01) and in lactate dehydrogenase (LDH) activity assay (p<0.01). Time course studies reveled that paliperidone effectively attenuated the elevation of intracellular free calcium concentration ([Ca2+]i) induced by exposure to MK-801 (p<0.01). Moreover, paliperidone could significantly retard MK-801-mediated inhibition of neurite outgrowth (p<0.01) and reverse MK-801-induced decreases of gene expression and phosphorylation of Akt1 and GSK3β (both p<0.01). Furthermore, these protective effects of paliperidone were blocked by pretreatment with a PI3K inhibitor LY294002. Taking together, our results demonstrated that paliperidone could protect prefrontal cortical neurons from MK-801-induced damages via Akt1/GSK3β signaling pathway.

Increased neuroinflammatory and arachidonic acid cascade markers, and reduced synaptic proteins, in the postmortem frontal cortex from schizophrenia patients

2013-04-08

Abstract: Schizophrenia (SZ) is a progressive, neuropsychiatric disorder associated with cognitive impairment. A number of brain alterations have been linked to cognitive impairment, including neuroinflammation, excitotoxicity, increased arachidonic acid (AA) signaling and reduced synaptic protein. On this basis, we tested the hypothesis that SZ pathology is associated with these pathological brain changes. To do this, we examined postmortem frontal cortex from 10 SZ patients and 10 controls and measured protein and mRNA levels of cytokines, and astroglial, microglial, neuroinflammatory, excitotoxic, AA cascade, apoptotic and synaptic markers. Mean protein and mRNA levels of interleukin-1β, tumor necrosis factor-α, glial acidic fibrillary protein (GFAP), a microglial marker CD11b, and nuclear factor kappa B subunits were significantly increased in SZ compared with control brain. Protein and mRNA levels of cytosolic and secretory phospholipase A2 and cyclooxygenase also were significantly elevated. N-methyl-d-aspartate receptor subunits 1 and 2B, inducible nitric oxide synthase and c-Fos were not significantly different. In addition, reduced protein and mRNA levels of brain-derived neurotrophic factor, synaptophysin and drebrin were found in SZ compared with control frontal cortex. Increased neuroinflammation and AA cascade enzyme markers with synaptic protein loss could promote disease progression and cognitive defects in SZ patients. Drugs that downregulate these changes might be considered for new therapies in SZ.

Transmembrane AMPA receptor regulatory protein (TARP) dysregulation in anterior cingulate cortex in schizophrenia

Jana B. Drummond, Janusz Tucholski, Vahram Haroutunian, James H. Meador-Woodruff — 2013-04-08

Abstract: The glutamate hypothesis of schizophrenia proposes that abnormal glutamatergic neurotransmission occurs in this illness, and a major contribution may involve dysregulation of the AMPA subtype of ionotropic glutamate receptor (AMPAR). Transmembrane AMPAR regulatory proteins (TARPs) form direct associations with AMPARs to modulate the trafficking and biophysical functions of these receptors, and their dysregulation may alter the localization and activity of AMPARs, thus having a potential role in the pathophysiology of schizophrenia. We performed comparative quantitative real-time PCR and Western blot analysis to measure transcript (schizophrenia, N=25; comparison subjects, N=25) and protein (schizophrenia, N=36; comparison subjects, N=33) expression of TARPs (γ subunits 1–8) in the anterior cingulate cortex (ACC) in schizophrenia and a comparison group. TARP expression was also measured in frontal cortex of rats chronically treated with haloperidol decanoate (28.5mg/kg every three weeks for nine months) to determine the effect of antipsychotic treatment on the expression of these molecules. We found decreased transcript expression of TARP γ-8 in schizophrenia. At the protein level, γ-3 and γ-5 were increased, while γ-4, γ-7 and γ-8 were decreased in schizophrenia. No changes in any of the molecules were noted in the frontal cortex of haloperidol-treated rats. TARPs are abnormally expressed at transcript and protein levels in ACC in schizophrenia, and these changes are likely due to the illness and not to the antipsychotic treatment. Alterations in the expression of TARPs may contribute to the pathophysiology of schizophrenia, and represent a potential mechanism of glutamatergic dysregulation in this illness.

Gyrification of Broca's region is anomalously lateralized at onset of schizophrenia in adolescence and regresses at 2year follow-up

2013-04-19

Abstract: Gyrification of the human cerebral cortex starts in the foetus and progresses in early infancy; the pattern of folding in later life provides a lead to early developmental aberration. By studying gyrification at illness onset in adolescence we hoped to clarify the pathophysiology of schizophrenia. Here we find 1) an area of hypergyria includes Broca's area and extends into the Sylvian fissure to encroach on the anterior insula in the left hemisphere, and 2) an area of hypogyria in the superior temporal lobe approximates to Wernicke's area but is located in the right hemisphere and encroaches on the posterior insula. In Broca's/anterior insula area, right lateralization was present in healthy controls but patients were left lateralized: at two year follow-up gyrification had decreased in patients while it increased in controls, and the reduction predicted impaired category fluency. Progressive change was unaccompanied by cortical thinning (investigated only in the brain regions showing baseline changes in gyrification) indicating that the disease process affecting these brain regions (insula, inferior frontal and superior temporal) is not primarily degenerative. A deviation in the lateralized development of peri-Sylvian areas for language production and comprehension appears critical to the pathophysiology of schizophrenia and may point to its species-specific origin.

Association of rs1344706 in the ZNF804A gene with schizophrenia in a case/control sample from Indonesia

2013-04-15

Abstract: Background: Association of rs1344706 in the ZNF804A gene (2q32.1) with schizophrenia was first reported in a genome wide scan conducted in a sample of 479 cases and replicated in 6666 cases. Subsequently, evidence by replication was obtained in several samples with European- and Asian ancestral background.Methods: We report ascertainment, clinical characterization, quality control, and determination of ancestral background of a case control sample from Indonesia, comprising 1067 cases and 1111 ancestry matched controls. Genotyping was performed using a fluorescence-based allelic discrimination assay (TaqMan SNP genotyping assay) and a newly designed PCR–RFLP assay for confirmation of rs1344706 genotypes.Results: We confirmed association of the T-allele of rs1344706 with schizophrenia in a newly ascertained sample from Indonesia with Southeast Asian ancestral background (P=0.019, OR=1.155, 95%, CI 1.025–1.301). In addition, we studied several SNPs in the vicinity of rs1344706, for which nominally significant results had been reported. None of the association P values of the additional SNPs exceeded that of rs1344706.Conclusion: We provide additional evidence for association of the ZNF804A gene with schizophrenia. We conclude that rs1344706 or a yet unknown polymorphism in linkage disequilibrium is also involved in conferring susceptibility to schizophrenia in samples with different (Asian) ancestral backgrounds.

Endocannabinoid metabolism in the prefrontal cortex in schizophrenia

David W. Volk, Benjamin I. Siegel, Christopher D. Verrico, David A. Lewis — 2013-04-04

Abstract: Adolescent cannabis use is associated with greater relative risk, increased symptom severity, and earlier age of onset of schizophrenia. We investigated whether this interaction may be partly attributable to disease-related disturbances in metabolism of the major cortical endocannabinoid 2-arachidonoylglycerol (2-AG). Transcript levels for the recently discovered 2-AG metabolizing enzyme, α-β-hydrolase domain 6 (ABHD6), were assessed using quantitative PCR in the prefrontal cortex of schizophrenia and healthy subjects (n=84) and antipsychotic- or tetrahydrocannabinol-exposed monkeys. ABHD6 mRNA levels were elevated in schizophrenia subjects who were younger and had a shorter illness duration but not in antipsychotic- or tetrahydrocannabinol-exposed monkeys. Higher ABHD6 mRNA levels may increase 2-AG metabolism which may influence susceptibility to cannabis in the earlier stages of schizophrenia.

Self-reported quality of life measure is reliable and valid in adult patients suffering from schizophrenia with executive impairment

2013-04-08

Abstract: Background: Impaired executive functions are among the most widely observed in patients suffering from schizophrenia. The use of self-reported outcomes for evaluating treatment and managing care of these patients has been questioned. The aim of this study was to provide new evidence about the suitability of self-reported outcome for use in this specific population by exploring the internal structure, reliability and external validity of a specific quality of life (QoL) instrument, the Schizophrenia Quality of Life questionnaire (SQoL18).Methods: Design: cross-sectional study. Inclusion criteria: age over 18years, diagnosis of schizophrenia according to the DSM-IV criteria. Data collection: sociodemographic (age, gender, and education level) and clinical data (duration of illness, Positive and Negative Syndrome Scale, Calgary Depression Scale for Schizophrenia); QoL (SQoL18); and executive performance (Stroop test, lexical and verbal fluency, and trail-making test). Non-impaired and impaired populations were defined for each of the three tests. For the six groups, psychometric properties were compared to those reported from the reference population assessed in the validation study.Results: One hundred and thirteen consecutive patients were enrolled. The factor analysis performed in the impaired groups showed that the questionnaire structure adequately matched the initial structure of the SQoL18. The unidimensionality of the dimensions was preserved, and the internal/external validity indices were close to those of the non-impaired groups and the reference population.Conclusions: Our study suggests that executive dysfunction did not compromise the reliability or validity of self-reported disease-specific QoL questionnaire.

Specific vs general cognitive remediation for executive functioning in schizophrenia: A multicenter randomized trial

2013-04-11

Abstract: Background: This study assesses the benefits of an individualized therapy (RECOS program) compared with the more general cognitive remediation therapy (CRT).Methods: 138 participants took part with 65 randomized to CRT and 73 to RECOS. In the RECOS group, participants were directed towards one of five training modules (verbal memory, visuo-spatial memory and attention, working memory, selective attention or reasoning) corresponding to their key cognitive concern whereas the CRT group received a standard program. The main outcome was the total score on BADS (Behavioural Assessment of Dysexecutive Syndrome) and the secondary outcomes were: cognition (executive functions; selective attention; visuospatial memory and attention; verbal memory; working memory) and clinical measures (symptoms; insight; neurocognitive complaints; self-esteem). All outcomes were assessed at baseline (T1), week 12 (posttherapy, T2), and follow-up (week 36, i.e., 6months posttherapy, T3).Results: No difference was shown for the main outcome. A significant improvement was found for BADS' profile score for RECOS at T2 and T3, and for CRT at T3. Change in BADS in the RECOS and CRT arms were not significantly different between T1 and T2 (+0.86, p=0.108), or between T1 and T3 (+0.36, p=0.540). Significant improvements were found in several secondary outcomes including cognition (executive functions, selective attention, verbal memory, and visuospatial abilities) and clinician measures (symptoms and awareness to be hampered by cognitive deficits in everyday) in both treatment arms following treatment. Self-esteem improved only in RECOS arm at T3, and working memory improved only in CRT arm at T2 and T3, but there were no differences in changes between arms.Conclusions: RECOS (specific remediation) and CRT (general remediation) globally showed similar efficacy in the present trial.

Persistence, diagnostic specificity and genetic liability for context-processing deficits in schizophrenia

Annette E. Richard, Cameron S. Carter, Jonathan D. Cohen, Raymond Y. Cho — 2013-04-08

Abstract: Context-processing deficits have been shown in schizophrenia during first-episode, medication-naïve status, that persist after short-term antipsychotic treatment and also in first-degree relatives of individuals with schizophrenia. To confirm longer term persistence of deficits, we examined schizophrenia patients (n=63) during first-episode, medication-naïve status through to one-year follow-up, compared to healthy control (n=83) and non-schizophrenia psychosis comparison (n=47) groups, as well as unaffected first-degree relatives of individuals with schizophrenia (n=31). Context-processing ability was assessed by performance on the AX-CPT (Continuous Performance Test) at baseline, 8weeks, 6months, and 1year (relatives only at baseline). Reaction time, error rates and signal detection indices (d′-context) of context processing were analyzed. Linear discriminant analyses (LDA) on early timepoints (baseline, 8weeks) were conducted to predict confirmatory diagnosis (schizophrenia vs. psychosis control) at 6months. Schizophrenia patients showed evidence of impaired context-processing relative to both the healthy and psychosis comparator groups at baseline and continued through to 1year. While context-processing impairments persisted in schizophrenia patients through one year, the impairments in psychosis controls, which were more modest at baseline, remitted at follow-up. First-degree relatives showed deficits that were intermediate between the schizophrenia and healthy control groups. LDA showed 67% classification rates for distinguishing schizophrenia from non-schizophrenia psychosis. The persistence, diagnostic specificity and association with genetic liability give support for context processing impairments serving as a cognitive endophenotype for schizophrenia and evaluation of context processing could contribute to diagnostic assessments.

Cognitive correlates of verbal memory and verbal fluency in schizophrenia, and differential effects of various clinical symptoms between male and female patients

2013-04-10

Abstract: Background: Impairment of higher cognitive functions in patients with schizophrenia might stem from perturbation of more basic functions, such as processing speed. Various clinical symptoms might affect cognitive efficiency as well. Notably, previous research has revealed the role of affective symptoms on memory performance in this population, and suggested sex-specific effects.Method: We conducted a post-hoc analysis of an extensive neuropsychological study of 88 patients with schizophrenia. Regression analyses were conducted on verbal memory and verbal fluency data to investigate the contribution of semantic organisation and processing speed to performance. The role of negative and affective symptoms and of attention disorders in verbal memory and verbal fluency was investigated separately in male and female patients.Results: Semantic clustering contributed to verbal recall, and a measure of reading speed contributed to verbal recall as well as to phonological and semantic fluency. Negative symptoms affected verbal recall and verbal fluency in the male patients, whereas attention disorders affected these abilities in the female patients. Furthermore, depression affected verbal recall in women, whereas anxiety affected it in men.Conclusions: These results confirm the association of processing speed with cognitive efficiency in patients with schizophrenia. They also confirm the previously observed sex-specific associations of depression and anxiety with memory performance in these patients, and suggest that negative symptoms and attention disorders likewise are related to cognitive efficiency differently in men and women.

The convergence between self-reports and observer ratings of financial skills and direct assessment of financial capabilities in patients with schizophrenia: More detail is not always better

2013-03-27

Abstract: Despite multiple lines of evidence suggesting that people with schizophrenia tend to overestimate their ability to perform everyday tasks such as money management, self-report methods are still widely used to assess functioning. In today's technology driven financial world patients are faced with increasingly complex financial management tasks. To meet these challenges adequate financial skills are required. Thus, accurate assessments of these abilities are critical to decisions regarding a patient's need for support such as a financial trustee. As part of the larger VALERO study, 195 patients with schizophrenia were asked to self-report their everyday financial skills (five common financial tasks) with the Independent Living Skills Survey (ILSS). They were also assessed with performance-based measures of neuro-cognition and functional capacity with a focus on financial skills. In addition, a friend, relative, or clinician informant was interviewed with the ILSS and a best estimate rating of functioning was generated. Scores on the performance-based measures of financial skills and neuropsychological tests were uncorrelated with self-reported financial activities. Interviewer and all informant judgments of financial abilities were also minimally correlated with performance on functional skill tests. Discrete financial skills appear to be challenging for clinicians to rate with accuracy without the use of direct assessments. Direct assessment of financial skills seems prudent when making determinations about the need for guardianship or other financial supervision.

Correlation between insight dimensions and cognitive functions in patients with deficit and nondeficit schizophrenia

Luiz F.L. Pegoraro, Clarissa R. Dantas, Claudio E.M. Banzato, Daniel Fuentes — 2013-03-27

Abstract: Previous studies have shown correlations between poor insight and neurocognitive impairment in schizophrenia. Deficit schizophrenia has been associated with worse cognitive functioning and poorer insight. This study aimed at investigating the relationship between insight dimensions (measured by Schedule for the Assessment of Insight—Expanded Version and its factors) and specific neurocognitive functions (assessed through a battery of neuropsychological tests) considering separately patients with deficit (n=29) and nondeficit schizophrenia (n=44), categorized according to the Schedule for the Deficit Syndrome. We found that working memory correlated positively and significantly with awareness of mental illness in both groups. In nondeficit group, awareness of mental illness correlated additionally with verbal fluency and attention. If confirmed by further studies, these results may have important consequences, such as the need of tailoring differently cognitive rehabilitation for each group.

Effectiveness of lurasidone vs. quetiapine XR for relapse prevention in schizophrenia: A 12-month, double-blind, noninferiority study

2013-04-15

Abstract: Objective: To evaluate the relapse prevention efficacy of lurasidone compared with quetiapine XR (QXR) in adults patients with schizophrenia.Method: This double-blind study evaluated the relapse prevention efficacy of 12months of flexible-dose treatment with lurasidone (40–160mg/day) compared with QXR (200–800mg/day), in outpatients with an acute exacerbation of chronic schizophrenia who had recently completed a 6-week placebo-controlled trial of treatment with either lurasidone or QXR. The primary endpoint, time-to-relapse, was analyzed using a Cox proportional hazards model in this noninferiority trial.Results: The Kaplan–Meier estimate of the probability of relapse over 12months was 23.7% for subjects receiving lurasidone vs. 33.6% for QXR. The hazard ratio [95% CI] for probability of relapse was 0.728 [0.410, 1.295] (log-rank p=0.280). Since the upper limit of the hazard ratio (1.295) was smaller than the prespecified noninferiority margin (1.93), noninferiority of lurasidone compared with QXR was demonstrated in this study. The probability of hospitalization at 12months was lower for the lurasidone group compared with the QXR group (9.8% vs. 23.1%; log-rank p=0.049). A significantly higher proportion of lurasidone subjects achieved remission at study endpoint compared with the QXR group (61.9% vs. 46.3%; p=0.043). Discontinuation rates due to AEs were similar for lurasidone and QXR (7% vs. 5%). Treatment with lurasidone was not associated with clinically significant changes in weight or metabolic parameters.Conclusions: Twelve months of treatment with lurasidone met noninferiority criteria, and was associated with higher rates of remission, and reduced risk of hospitalization compared with QXR. No clinically significant effects on weight or metabolic parameters were observed during maintenance treatment with lurasidone.

Antipsychotics can modulate the cytokine profile in schizophrenia: Attenuation of the type-2 inflammatory response

2013-04-18

Abstract: Objective: We recently reported that the type-2 cytokine response is increased in schizophrenia. The aim of this study was to analyse the effects of antipsychotic drugs on the serum levels of type-1 (TNF-α, IFN-γ), type-2 (IL-4, IL-10), type-17 (IL-17) and regulatory cytokines (TGF-β, IL-27 and IL-6).Methods: Cytokine measurements in the patients were performed on day 0 and day 30 of the treatment using standard ELISA assays. Three groups of subjects were studied: patients that were unmedicated with First Episode Psychosis (FEP; n=88), patients that were treated with antipsychotics with Schizophrenia in relapse (SC in relapse; n=45) and healthy controls (n=36).Results: TGF-β levels were increased in both patient groups and were further enhanced after treatment in the FEP group (p=0.014) but not in the SC relapse group. Antipsychotic treatment was correlated with lower levels of IL-4, IL-6 and IL-27 (p<0.005) in the FEP group. Finally, the serum levels of IL-17 were not significantly altered between the two measurements but were significantly lower in the FEP group (p<0.001) when compared with healthy controls. After therapy, patients with SC who were in relapse had decreased serum levels of IL-4 (p=0.006) and IL-6 (p=0.007). We also observed a weak negative correlation between the IFN-γ/TGF-β ratio and the total PANSS score and between the IL-17/TGF-β ratio and the negative and general psychopathology subscales.Conclusion: The increased type-2 cytokine serum levels in schizophrenia appear to be downregulated by antipsychotic treatment.

The effect of zonisamide on antipsychotic-associated weight gain in patients with schizophrenia: A randomized, double-blind, placebo-controlled clinical trial

Ahmad Ghanizadeh, Mohammad Saeed Nikseresht, Ali Sahraian — 2013-04-15

Abstract: Background: Many patients with schizophrenia suffer from metabolic symptoms and weight gain in which predispose them to obesity, diabetes, and cardiovascular problems.This trial examines the efficacy and safety of zonisamide on weight and body mass index in patients with schizophrenia being administered with atypical antipsychotics.Method: In this 10-week, double blind randomized placebo controlled clinical trial, forty one patients with schizophrenia diagnosed according to DSM-IV-TR criteria who were taking a stable dose of atypical antipsychotic are allocated into one of the two groups of zonisamide or placebo group. Weight, body mass index, waist circumference, and adverse effects were assessed.Results: The two groups were not statistically different regarding baseline characteristics on age, gender, education, diagnosis, weight, body mass index, daily cigarette smoking, and the duration of illness. After 10weeks, the patients in the placebo group had significantly gained weight, while the patients in the zonisamide group lost weight (mean=1.9, SD=2.2 versus mean=−1.1kg, SD=1.4). The changes of body mass index in the two groups were significantly different. Body mass index decreased in the zonisamide group (mean=−0.3, SD=0.4) while it increased in the placebo group (mean=2.2, SD=6.9). There was a significance difference between the two groups regarding waist circumference at the end of trial (P<0.0001), too. The waist increased in the placebo group while it decreased in the zonisamide group (mean=1.1, SD=1.7 versus mean=−0.7, SD=1.2, respectively), as well.The frequencies of adverse effects were not significantly different between the two groups and zonisamide was tolerated well.Conclusion: Zonisamide as an adjuvant treatment is tolerated well and markedly affect on the weight loss of patients with schizophrenia being treated with atypical antipsychotics.

The low- and higher-order factor structure of symptoms in patients with a first episode of psychosis

Victor Peralta, Lucía Moreno-Izco, Laura Calvo-Barrena, Manuel J. Cuesta — 2013-04-12

Abstract: Background: The phenotype of psychotic disorders is presumed to be heterogeneous, but the best way to describe this heterogeneity remains unclear.Objective: To examine the lower-order and higher-order symptomatic architecture of psychotic disorders by means of factor analysis and the Schmid–Leiman transformation.Methods: Patients experiencing their first episode of psychosis (n=486) were comprehensively examined for 70 symptomatic variables, which were subjected to principal components analysis followed by a Promax rotation. First-order factors were subjected to second-order factor analysis, and influence of second-order factors on primary factors was removed using the Schmid–Leiman transformation.Results: First-order factor analysis revealed 13 primary factors that were substantially intercorrelated. Second-order factor analysis showed 5 higher-order factors with no substantial intercorrelations. The Schmid–Leiman transformation revealed that whereas the second-order factors accounted for most of the symptom covariance (63.5%), the first-order factors still accounted for an additional 36.5%. According to this transformation, five second-order factors (bipolar negative-mania, disorganization, psychomotor retardation, hallucinations and grandiosity) plus four first-order factors (depression, catatonia, bizarre delusions and paranoid delusions) best explained the factor structure of the symptoms.Conclusions: The phenotype of psychosis is more complex than previously acknowledged as it embraces a multidimensional hierarchical structure organized into nonredundant first- and second-order factors.

Symptom dimensions and functional impairment in early psychosis: More to the story than just negative symptoms

2013-04-15

Abstract: Functional impairment is a defining feature of psychotic disorders and usually appears well before their onset. Negative symptoms play a prominent role in the impaired functioning of individuals with schizophrenia and those at clinical-high-risk (CHR) for psychosis. Despite high rates of depression and anxiety in early psychosis, few studies have examined the contribution of these symptoms to functioning in the putative ‘prodrome.’ In the current study, we tested the hypotheses that 1) worse negative and disorganized, but not positive, symptoms would be significantly related to impaired social and role functioning in two cohorts of CHR individuals (combined N=98) and a separate sample of individuals with recent-onset (RO) psychotic disorders (N=88); and 2) worse anxiety and depression would be significantly related to impaired functioning in both samples, above and beyond the contributions of negative and disorganized symptoms. Findings largely supported our hypotheses that more severe negative and disorganized symptoms were related to poorer social and role functioning in both samples. Anxiety and depression severity were significantly related to poorer functioning in both samples. In addition, depression, but not anxiety, predicted poorer global and social functioning above and beyond that explained by negative symptoms in the CHR sample. These results suggest the need for phase-specific treatment in early psychosis, with a focus on symptom dimensions to improve functional outcomes for CHR individuals.

Comorbid substance abuse in first-episode schizophrenia: Effects on cognition and psychopathology in the EUFEST study

2013-03-27

Abstract: Studies and meta-analyses investigating the influence of substance use disorder (SUD) (substance abuse or dependence) on psychopathology and neurocognitive function in schizophrenia patients have revealed controversial results. Most studies did only have small samples and did not focus exclusively on first-episode schizophrenia patients.Method: In a post-hoc analysis of the European First Episode Schizophrenia Trial (EUFEST) psychopathology and cognitive performances of patients with (FE-SUD, N=119, consisting of N=88 patients with persisting SUD at baseline and N=31 patients with previous SUD) and without SUD (FE-non-SUD, N=204) were compared at baseline and 6months follow-up. Neurocognitive assessment included the Rey Auditory Verbal Learning Test (RAVLT); Trail Making Tests A and B (TMT), Purdue Pegboard and Digit-Symbol Coding.Results: In total 31.1% of patients reported SUD, and 22.2% of patients used cannabis. There were no significant differences between patients with and without SUD concerning PANSS scores, extrapyramidal motor symptoms or neurocognitive measures except better performance in psychomotor speed (TMT-A, p=0.033, Cohen's d=0.26) in patients with SUD at 6months follow-up. Interestingly, SUD patients with ongoing substance use at follow-up showed elevated positive symptoms (PANSS positive score, p=0.008, Cohen's d=0.84) compared to those who abstained. PANSS scores at baseline were increased in patients with an onset of SUD before the age of 16years. In addition we found a correlation between longer duration of cannabis use and higher cognitive performance as well as reduced symptom improvement and more extrapyramidal motor symptoms in patients with higher frequency of cannabis consumption.Conclusions: FE-SUD and FE-non-SUD show similar psychopathology and neuropsychological performances at baseline and during the first 6months of antipsychotic treatment.

Schizophrenia susceptibility and age of diagnosis — A frailty approach

2013-03-28

Abstract: Background: Using a frailty model approach, we aim to evaluate the effect of early-life risk factors on susceptibility and age at diagnosis of schizophrenia. We assume paternal age and familial schizophrenia influence the susceptibility, while these and several early risk factors influence the age of diagnosis.Method: Schizophrenia incidence data were derived from the population-based Swedish Patient Registry; including individuals aged 18 to 45years, diagnosed between 1974 and 2008. Data were analyzed by a frailty model, a random effects model in survival analysis, using a compound Poisson model.Results: 15,340 incident schizophrenia cases were included. For individuals without familial schizophrenia, a protective effect was seen across most ages of diagnosis for females, low paternal age, born in rural areas, and being born in later cohorts. For individuals with familial schizophrenia, a protective effect is found for females diagnosed between ages 18 and 30years, corresponding values were 18–25years for low paternal age. Being born in rural areas and in the last birth cohort was protective for all. The estimated proportion of susceptible was 5% for those without familial schizophrenia and 18% for individuals with familial schizophrenia. There was no statistically significant effect of paternal age on the proportion of susceptible.Discussion: To our knowledge, this is the first regression modeling of time to schizophrenia diagnosis allowing for a non-susceptible fraction of the population, including age dependent modeling of covariate effects and an interaction. Applying frailty model to schizophrenia provide etiological clues, elucidating patterns of susceptibility and age-at-diagnosis for which early-life factors are of importance.

Parent–adolescent agreement on psychosis risk symptoms

2013-04-08

Abstract: Despite practice guidelines recommending caregiver inclusion for assessment of mental health problems in adolescents, clinical high-risk (CHR) assessment tools that target attenuated psychosis symptoms rely solely on self-report. As many individuals in the clinical high-risk phase are expected to be adolescents, and programs of CHR research routinely recruit participants as young as twelve, parent input regarding adolescents' symptoms and functioning may help to inform clinical conceptualizations. No assessment tool targeting CHR symptoms has been developed for this purpose. We created a caregiver-report version of the 12-item Prime Screen-Revised and administered the measure to caregivers of 52 youth ages 12–19 referred by mental health providers for CHR study participation. Youth completed the Prime Screen-Revised as well as the Structured Interview for Psychosis Risk Syndromes (SIPS). Caregiver responses demonstrated poor agreement with youth ratings on Prime Screen-Revised (r=.09), but moderate agreement with clinician ratings (r=.41). The addition of caregiver screening data to youth self-report scores significantly improved a linear regression predicting clinician ratings. Using a threshold of four or more endorsements, the combined use of parent and adolescent responses accurately classified 75% of respondents with regard to SIPS-determined CHR status. Findings suggest that involving caregivers may help to improve the specificity of CHR screening and assessment procedures.

Broadly defined risk mental states during adolescence: Disorganization mediates positive schizotypal expression

Martin Debbané, Deborah Badoud, Dario Balanzin, Stephan Eliez — 2013-04-08

Abstract: While schizotypal features are common during adolescence, they can also signal increased risk for the onset of schizophreniform disorders. Most studies with adolescents find that hallucination and delusion-like symptoms (positive schizotypal features) best predict future psychopathology. Still, the developmental process of positive schizotypy remains elusive, specifically with regards to 1) its relationships to negative and disorganization schizotypal dimensions; 2) its associations to maladaptive functioning during adolescence. This longitudinal study aimed to further characterize these relationships, thereby delineating “early and broadly defined psychosis risk mental states” ().The current study presents the 3-year course of schizotypal trait expression in 34 clinical adolescents aged 12 to 18years consulting for non-psychotic difficulties. Schizotypal expression was assessed twice using the Schizotypal Personality Questionnaire, accompanied by an examination of internalizing/externalizing problems using the Achenbach scales. Cross-sectional and longitudinal analyses were conducted to assess the expression and course of schizotypal dimensions; mediation analyses were further employed to highlight the developmental interactions promoting the maintenance of positive schizotypal expression.The results reveal that positive schizotypy, and more specifically unusual perceptual experiences, significantly declined during the study interval. Disorganization features were found to mediate the relationships between the negative and positive dimensions of schizotypy within and across evaluations. Somatic complaints and attentional difficulties further strengthened the expression of positive schizotypy during the study interval. These results suggest that the relationship between disorganization features and positive schizotypy may play a central role in establishing risk for psychosis during adolescence.

Categorical and dimensional approaches to negative symptoms of schizophrenia: Focus on long-term stability and functional outcome

2013-04-22

Abstract: Negative symptoms of schizophrenia represent a heterogeneous psychopathological domain. Both categorical and dimensional approaches have been proposed to reduce negative symptoms heterogeneity.In the present 5-year follow-up study, long-term stability and impact on outcome of different aspects of negative symptoms were investigated. Following a categorical approach, long-term stability and outcome of deficit schizophrenia (DS), in comparison with nondeficit schizophrenia (NDS), were assessed. Following a dimensional approach, the factor structure and stability of broadly defined negative symptoms and the ability of the identified factors to predict functional outcome were investigated.DS and NDS subjects included in a previous study were invited to participate. Fifty-one out of 58 patients previously diagnosed as DS and 44 out of 54 NDS patients were included in the present study.The DS/NDS categorization was confirmed in 82.4% of DS and 79.6% of NDS subjects. At follow-up, DS patients showed more severe negative symptoms and greater social dysfunction than NDS ones.Schedule for the Deficit Syndrome (SDS) severity scores loaded on two factors: “Poor Emotional Expression” and “Avolition” and the factor structure was stable after 5years. Avolition was associated to social outcome measures and Poor Emotional Expression to functioning in household activities.Psychosocial outcome was predicted by SDS factors reflecting the severity of broadly defined negative symptoms, but not by the DS/NDS categorization. This might lend support to the recent shift of research focus from the categorical approach focusing on the presence of primary and enduring negative symptoms to the investigation of key domains of broadly defined negative symptoms.

Predicting compliance with command hallucinations: Anger, impulsivity and appraisals of voices' power and intent

2013-03-27

Abstract: Command hallucinations are experienced by 33–74% of people who experience voices, with varying levels of compliance reported. Compliance with command hallucinations can result in acts of aggression, violence, suicide and self-harm; the typical response however is non-compliance or appeasement. Two factors associated with such dangerous behaviours are anger and impulsivity, however few studies have examined their relationship with compliance to command hallucinations. The current study aimed to examine the roles of anger and impulsivity on compliance with command hallucinations in people diagnosed with a psychotic disorder. The study was a cross-sectional design and included individuals who reported auditory hallucinations in the past month. Subjects completed a variety of self-report questionnaire measures. Thirty-two people experiencing command hallucinations, from both in-patient and community settings, were included. The tendency to appraise the voice as powerful, to be impulsive, to experience anger and to regulate anger were significantly associated with compliance with command hallucinations to do harm. Two factors emerged as significant independent predictors of compliance with command hallucinations; omnipotence and impulsivity. An interaction between omnipotence and compliance with commands, via a link with impulsivity, is considered and important clinical factors in the assessment of risk when working with clients experiencing command hallucinations are recommended. The data is highly suggestive and warrants further investigation with a larger sample.

Differences between first episode schizophrenia and schizoaffective disorder

2013-03-26

Abstract: Background: The diagnostic and clinical overlap between schizophrenia and schizoaffective disorder is an important nosological issue in psychiatry that is yet to be resolved. The aim of this study was to compare the clinical and functional characteristics of an epidemiological treated cohort of first episode patients with an 18-month discharge diagnosis of schizophrenia (FES) or schizoaffective disorder (FESA).Methods: This study was part of the larger First Episode Psychosis Outcome Study (FEPOS) which involved a medical file audit study of all 786 patients treated at the Early Psychosis Prevention and Intervention Centre between 1998 and 2000. Of this cohort, 283 patients had an 18-month discharge diagnosis of FES and 64 had a diagnosis of FESA. DSM-IV diagnoses and clinical and functional ratings were derived and validated by two consultant psychiatrists.Results: Compared to FES patients, those with FESA were significantly more likely to have a later age of onset (p=.004), longer prodrome (p=.020), and a longer duration of untreated psychosis (p<.001). At service entry, FESA patients presented with a higher illness severity (p=.020), largely due to the presence of more severe manic symptoms (p<.001). FESA patients also had a greater number of subsequent inpatient admissions (p=.017), had more severe depressive symptoms (p=.011), and higher levels of functioning at discharge.Discussion: The findings support the notion that these might be considered two discernable disorders; however, further research is required to ascertain the ways and extent to which these disorders are discriminable at presentation and over time.

A brief version of the Subjects' Response to Antipsychotics questionnaire to evaluate treatment effects

2013-04-04

Abstract: Background: Monitoring patients' experiences with antipsychotics may help to improve medication adherence and outcome. We aimed to develop a shorter version of a comprehensive 74-item self-report questionnaire suitable for routine monitoring of desired and undesired effects of antipsychotics.Methods: Included were patients with psychotic disorders from seven mental health care organizations in The Netherlands, using antipsychotic medication, who completed the Subjects' Response to Antipsychotics (SRA-74). Exploratory factor analysis (EFA) and similarity analysis based on mutual information were used to identify the latent factor structure of the SRA. Items were reduced according to their metric properties and clinical relevance upon consensus by an expert panel, using a Delphi procedure of three rounds. We determined the internal consistency of the shorter version using Cronbach's alpha.Results: SRA data of N=1478 patients (mean age of 40years, 31% females) were eligible for analysis. EFA extracted thirteen factors from the SRA-74, including four factors for desired effects (e.g. recovery of psychosis, cognition and social functioning) and nine factors for undesired effects (e.g. weight gain, flattened affect and increased sleep). Based on this solution 12 items were eliminated for statistical reasons. The expert panel eliminated another 28 items with redundant content, resulting in a 34-item version. The SRA-34 includes 10 desired and 24 clinically relevant undesired effects. Both the subscales for desired and undesired effects have a Cronbach's alpha coefficient of 0.82.Conclusions: The SRA-34 can be used to evaluate desired and undesired effects of antipsychotics in routine clinical practice and research.

Pragmatic use of language by children who develop schizophrenia in adult life

D. John Done, Eeva Leinonen — 2013-04-04

Abstract: At eleven years of age all children in a UK national birth cohort wrote short stories about the life they expected to be leading at age 25.Using a data linkage exercise, we identified those who later developed schizophrenia, affective psychosis, or other non-psychotic psychiatric disorders in later life based on the PSE CATEGO diagnostic system. The majority of these had completed the written essays. Controls from the reference population were selected, matched for gender, IQ and social and economic status.The essays were scored using well established methods for assessing pragmatic use of language, namely narrative coherence and linguistic cohesion.We hypothesised that children pre-morbid for schizophrenia (Pre-Scz) would obtain low scores on all these measures. However this general hypothesis was largely disproved by the data, although some unpredicted gender effects were found.It is concluded that thought is organised in an unexceptional way in adolescents before they develop schizophrenia, once the data are corrected for any lowering of general cognitive ability in the Pre-Scz cases.

Increased Framingham 10-year CVD risk in Chinese patients with schizophrenia

Yi Hang Tay, Milawaty Nurjono, Jimmy Lee — 2013-04-15

Abstract: Background & hypothesis: Schizophrenia is associated with increased mortality rates, which has been attributed to the greater incidence of cardiovascular disease (CVD) events. The Framingham risk score (FRS) is a widely-used age- and gender-specific algorithm to estimate 10-year CVD risk and vascular age. The main aim of this study was to determine the cardiovascular risk profile in schizophrenia and examine the effect of metabolic syndrome (MetS) as a predictor of CVD risk. We hypothesized that patients with schizophrenia have an increased 10-year CVD risk.Methods: 83 Chinese patients with schizophrenia and 243 Chinese community controls were recruited. Their medical and smoking histories were obtained, and anthropometric parameters measured. All subjects provided fasted venous blood samples for lipid and glucose measurements. 10-year CVD risk and the difference between vascular and actual age (VAdiff) for each participant were computed using the FRS and compared between patients and controls.Results: Schizophrenia patients had a higher mean 10-year CVD risk of 4.6%, as compared with 3.1% in controls, and a greater VAdiff of 4.6years vs. 0.6years. Both smoking and MetS contributed significantly to the 10-year CVD risk in patients with schizophrenia, with smoking having a greater effect than MetS on this risk.Conclusion: This study found a significantly elevated mean 10-year CVD risk and VAdiff in patients with schizophrenia compared with controls. Findings point towards the importance of smoking cessation and screening for MetS to decrease the excess CVD risk in patients with schizophrenia.

Increased prevalence of psychotic disorders among third-generation migrants: Results from the French Mental Health in General Population survey

2013-04-08

Abstract: There is very strong evidence that the prevalence of psychosis is elevated in migrant populations and that this risk persists into the second generation. However, these results have not been replicated in France, and the prevalence of psychotic disorders in the third generation of migrants remains unknown. Based on the Mental Health in General Population survey (n=37063), we report for the first time the increased prevalence of psychotic disorders in migrants in France, which persists into the second generation for a single psychotic episode (SPE) (OR=1.43, 95% CI [1.02–2.03], p<0.03) and into the third generation for recurrent psychotic disorder (RPD) (OR=1.78, 95% CI [1.45–2.18], p<0.0001) after adjustment for age, sex, level of education and cannabis use. Complementary statistical analyses of our sample showed a significantly higher risk of SPE in migrants from the French West Indies and Africa (χ2=17.70, p<0.01). These results are consistent with the socio-developmental model and the psychosis continuum hypothesis.

Early sensory processing deficits predict sensitivity to distraction in schizophrenia

Jason Smucny, Ann Olincy, Lindsay C. Eichman, Emma Lyons, Jason R. Tregellas — 2013-04-15

Abstract: Patients with schizophrenia frequently report difficulties paying attention during important tasks, because they are distracted by noise in the environment. The neurobiological mechanism underlying this problem is, however, poorly understood. The goal of this study was to determine if early sensory processing deficits contribute to sensitivity to distracting noise in schizophrenia. To that end, we examined the effect of environmentally relevant distracting noise on performance of an attention task in 19 patients with schizophrenia and 22 age and gender-matched healthy comparison subjects. Using electroencephalography, P50 auditory gating ratios also were measured in the same subjects and were examined for their relationship to noise-induced changes in performance on the attention task. Positive symptoms also were evaluated in patients. Distracting noise caused a greater increase in reaction time in patients, relative to comparison subjects, on the attention task. Higher P50 auditory gating ratios also were observed in patients. P50 gating ratio significantly correlated with the magnitude of noise-induced increase in reaction time. Noise-induced increase in reaction time was associated with delusional thoughts in patients. P50 ratios were associated with delusional thoughts and hallucinations in patients. In conclusion, the observation of noise effects on attention in patients is consistent with subjective reports from patients. The observed relationship between noise effects on reaction time and P50 auditory gating supports the hypothesis that early inhibitory processing deficits may contribute to susceptibility to distraction in the illness.

A study to evaluate the effect of celecoxib as add-on to olanzapine therapy in schizophrenia

2013-04-15

The concept of immunological/inflammatory pathogenesis has gained acceptance recently and alterations in the level of cytokines have been described in the etiology of schizophrenia (). Recent studies show that the use of a COX-2 inhibitor, celecoxib, as an adjunct to risperidone () or amisulpride () in the treatment of schizophrenia is beneficial. We conducted an open-labeled, prospective, 6-week controlled trial of two parallel groups of patients suffering from acute exacerbation of schizophrenia from August 2010 to July 2011. Patients were assigned to treatment with either olanzapine (group A) or olanzapine with celecoxib (group B) by simple alternate allocation. Subjects were inducted from the outpatient department of psychiatry of a university teaching hospital in Lucknow (Northern India). This study was approved by the Institutional Ethics Committee of the Medical University and written informed consent from the patient and/or assent from his/her primary caregiver was taken.

Antipsychotic drugs decrease iPLA2 gene expression in schizophrenia

2013-04-15

Increased phospholipase A2 (PLA2) activity has been frequently reported in schizophrenia, whereas treatment with anti-psychotic drugs was found to reduce the enzyme activity to levels similar to those observed in control subjects (). However the mechanisms underlying this reduction are not yet understood. The PLA2 family of enzymes is composed by three main groups: calcium-independent intra-cellular PLA2 (iPLA2), calcium-dependent secretory PLA2 (sPLA2) and calcium-dependent cytosolic PLA2 (cPLA2) (). To date, 27 genes and 2 pseudogenes have been identified as PLA2 subtypes at the NCBI Gene database (http://www.ncbi.nlm.nih.gov/gene, December 2011). In the present study we evaluated in schizophrenia patients and in healthy controls the mRNA expression from 10 of those genes for which Taqman assays were available.

Postictal sympathetic response to electroconvulsive therapy in patients with schizophrenia

Tetsufumi Suda, Aihide Yoshino, Tatsuro Kuwahara, Soichiro Nomura — 2013-04-08

Previously we had reported the cases of 3 patients with schizophrenia who abruptly developed severe tachycardia, atrial fibrillation, and hypertension approximately 10min after the termination of electroconvulsive therapy (ECT)-induced seizure (). Generally, ECT-induced seizure produces sympathetic excitation such as a dramatic rise in the blood pressure and heart rate (HR) which continues until the seizure terminates (). However, this ictal sympathetic response cannot explain our anecdotal findings of the postictal sympathetic hyperactivity. This study was conducted to confirm the reproducibility of our case series by using heart rate variability (HRV) as an index of autonomic function. We compared the change in HRV after termination of ECT-induced seizures in patients with schizophrenia with that in patients with mood disorders.

Change in jumping to conclusions linked to change in delusions in early psychosis

Nicole Sanford, Tania Lecomte, Claude Leclerc, Til Wykes, Todd S. Woodward — 2013-04-04

Symptom-related cognitive biases such as jumping to conclusions (JTC) can potentially be the focus of cognitive therapies such as cognitive behavioural therapy for psychosis (CBTp; ) and metacognitive training (MCT; ). To provide support for such an approach it is important to demonstrate correspondence between change in delusions and change in JTC. JTC studies typically employ the beads task, where an individual is presented with two jars containing different ratios of beads of two colours, and is asked to decide from which jar a series of beads are being drawn. A cross-sectional association between delusions and JTC is a well replicated finding in cognitive neuropsychiatry research. In past work, we demonstrated a correspondence between change in delusions and change in JTC (). In the current study we attempted to replicate our previous finding (), but this study design is complicated by (1) miscomprehension of the task when drawn bead colours vary (), and (2) quicker decisions when the study design involves closely-spaced testing sessions (). Therefore, we investigated correspondence between change in delusions and change in JTC using a series with a uniform colour to facilitate comprehension (), combined with a longer time interval (6months in addition to the typical 12weeks) to minimize learning effects.