Abstract: Background: Little is known about the suicide risk of older adults diagnosed with schizophrenia. The purpose of the study is to examine whether older adults diagnosed with schizophrenia have an elevated risk of dying by suicide, examine trends by age, and identify predictors of death by suicide.Methods: Individual-level register data on all older adults aged 50+ living in Denmark during 1990–2006 (N=2,899,411) were assessed using survival analysis. The impact of predictors was adjusted for a series of socio-demographic and health-related covariates.Results: In all, 248 suicides were identified among older adults diagnosed with schizophrenia. The suicide rate ratios of men and women aged 50–69years with a diagnosis of schizophrenia was 7.0 [95%CI: 5.8–8.4] and 13.7 [95%CI: 11.3–16.6], respectively, when compared to those with no diagnosis. With increasing age a lower rate ratio was found; for men and women aged 70+ it was 2.1 [95%CI: 1.1–3.9] and 3.4 [95%CI: 2.0–5.8], respectively. Adjusted analyses revealed an elevated risk of suicide for diagnoses of schizophrenia, greater number of hospitalizations, recent admission (for men), recent discharge, previous suicide attempt, recent suicide attempt, comorbidity of mood disorders, personality disorders, and substance abuse (for women).Conclusions: We found an elevated mortality risk of suicide for both men and women aged 50years and over diagnosed with schizophrenia. Health care staff should be aware of elevated risk, particularly in older women diagnosed with schizophrenia, in relation to chronic disease courses, recent discharge, and suicide attempt.
Abstract: Behavioral abnormalities related to processing negative emotions such as fear have been demonstrated in schizophrenia. The amygdala is strongly associated with fear processing, and alterations in amygdala function and structure have been demonstrated in schizophrenia. Further, functional disconnectivity has been attributed as key to the etiology of schizophrenia, with a number of lines of evidence supporting this theory. In the present study, we examine the effective connectivity corresponding to fear processing, from the amygdala to the whole brain, and compare this between patients with schizophrenia and control participants. An implicit facial emotion processing task was performed by 19 patients with schizophrenia and 24 matched controls during fMRI scanning. During the task, participants made gender judgments from facial images with either neutral or fearful emotion. Neural response to fearful images versus neutral was used as contrast of interest to estimate effective connectivity between the amygdala and the whole brain using the psycho-physiological interactions approach. This connectivity was compared between patients with schizophrenia and healthy controls. We show that when looking at fearful compared to neutral faces patients with schizophrenia show significantly reduced effective connectivity from the amygdala to a large cluster of regions including parts of the precuneus and parietal lobe, compared to healthy controls. These regions have been associated with emotion processing and high level social cognition tasks involving self related processing and mental representations about other people. The reduced amygdala connectivity in schizophrenia shown here further illuminates the neural basis for the behavioral abnormalities in emotional and social function found in the disorder.
Abstract: Background: Are anomalies of cerebral asymmetry integral to the disease process? Here, we examined the influence of age, chronicity and age of onset of illness in 34 patients with early onset schizophrenia and 20 controls in relation to structural asymmetries of the temporal lobe and performance asymmetries on a semantic language lexical decision task.Methods: Volumetric MRI and a novel divided visual field probe of lateralised lexico-semantic language were assessed in patients with early onset schizophrenia (EOS) and controls. Novel ratios of age–illness overlap and directional asymmetry were developed in order to examine the association of chronicity factors to asymmetry.Results: Loss of laterality on the lexical decision task and discordant structural asymmetry were correlated with duration of illness but were not seen in younger, less chronic patients. Reduced lateral processing speed, and discordant structural asymmetry were associated with greater proportion of lifetime schizophrenia.Conclusion: Although the conclusions are limited by the cross sectional nature of the study, anomalies of cerebral asymmetry in early onset patients may be an index of disease progression, and reflect directly on the disease process.
Abstract: Introduction: A consistent brain imaging finding in schizophrenia is decreased language-asymmetry, already evident in first episode patients, thus arguing for a biomarker of the disorder. Nonetheless, its specificity to schizophrenia is questionable. Furthermore, while previous studies suggested that enhanced right hemisphere activation underlies this diminished asymmetry, the mechanism for this anomaly is yet unknown. This study aimed to examine the role of inter-hemispheric relations in such abnormality through functional connectivity analysis driven by left inferior frontal gyrus (IFG) activation. To test for disorder specificity we compared schizophrenia patients not only to healthy controls but also to patients with obsessive compulsive disorder (OCD).Methods: Functional magnetic resonance imaging (fMRI) was applied during an auditory verb generation task in the 3 groups. Language-related activation in BA44/45 located in the IFG was used for regional estimation of brain asymmetry and for assessment of inter-hemispheric functional connectivity.Results: Schizophrenia, but not OCD patients showed reduced language asymmetry in the IFG relative to healthy controls and diminished functional connectivity between the left and right IFG. Importantly, decreased inter-hemispheric functional connectivity in the IFG was related to more negative symptoms among the schizophrenia patients.Conclusions: Diminished language-related asymmetry in the IFG seems to be an early disorder specific neural marker of schizophrenia, supporting its pathogenic role. The relation of this regional abnormality to reduced inter-hemispheric functional connectivity and symptom severity supports the role of large-scale brain disorganization in schizophrenia. This may relate to the known structural abnormalities of the corpus callosum leading to functional hemispheric dysconnection.
Abstract: The etiology of schizophrenia has been proposed to be neurodevelopmental based on neuroimaging and molecular biological studies. If there is neuronal vulnerability based on neurodevelopment failures in schizophrenic brains, then the impact of aging may have a greater effect on schizophrenic brains than on normal brains. To determine the impact of aging on schizophrenic brains, we investigated the age-related morphological changes of the cross-sectional area of the gray matter (GM) in the left Heschl’s gyrus (HG) and the left superior gyrus (STG) in 22 schizophrenic and 24 age- and sex-matched normal control postmortem brains two-dimensionally. The subject groups were divided into younger groups (30–54years of age) and older groups (65–84years of age) on the basis of age at death. Both in schizophrenic and control subjects, the GM area in HG and the STG was significantly smaller in the older group than in the younger group, however, no significant differences were observed between the schizophrenic and control subjects. In the STG, the cross-sectional area of the white matter (WM) was also measured. In the older group, the ratio of the GM area to the WM area in the STG was significantly larger in schizophrenic subjects than controls, although there was no significant difference between the schizophrenic and control subjects in the younger group. These findings indicate that the impact of aging has a greater effect on the WM in the STG in schizophrenic subjects than in normal individuals, although the pathological basis is still unclear.
Abstract: Background: Previous studies have shown that patients with schizophrenia show abnormalities in brain activation when processing emotional faces. However, very few studies have examined if such abnormalities are also found in non-western patient samples and in at-risk individuals. The current study explored whether patients with schizophrenia and siblings of patients in China would show abnormal brain activation during processing of emotional faces.Methods: Thirty-six participants (three groups of twelve each of patients with schizophrenia, nonpsychotic siblings, and healthy controls) took part in the study. They were administered a task to judge emotional valence of three types of faces (viz., happy, fearful, and neutral), during fMRI scanning.Results: Results of this study demonstrated that patients with schizophrenia showed abnormalities in the social brain neural circuit during facial emotion processing, in comparison with nonpsychotic siblings and healthy controls. Patients with schizophrenia demonstrated lower activation right superior and middle frontal gyrus, left precentral gyrus, left middle temporal gyrus and left insula in comparison with healthy controls; and showed abnormal activation in bilateral inferior and middle frontal gyri, right orbital frontal gyrus, left superior and middle temporal gyrus, bilateral insula, and right superior parietal gyrus/postcentral gyrus when compared with their nonpyschotic siblings. Meanwhile, patients with schizophrenia showed greater activation in left middle frontal gyrus than healthy controls, and overactivation in bilateral middle frontal gyri, right orbital frontal gyrus and left middle temporal gyrus than their nonpsychotic siblings during processing of fearful faces. Moreover, nonpsychotic siblings seemed to share some similar dysfunctions in processing facial expressions as their psychotic probands, the two groups both showed abnormal activation in precentral and superior frontal gyri, and such abnormal activation lied between patients with schizophrenia and healthy controls.Conclusions: The current findings support the universality of emotion perception impairments in schizophrenia, and also suggest that facial emotion perception might be a potential endophenotype of schizophrenia.
Abstract: The occurrence of weight gain in schizophrenia (SZ) has profound clinical impact and interacts with antipsychotic medication, life style and disease severity. The functional neuroanatomy underlying altered nutritional behavior is unraveled, but dysregulated reward anticipation might be one of the involved neuronal mechanisms. The striatum, a core region of the reward network and salience attribution, was previously shown to regulate appetite perception and eating behavior. We studied patients suffering from chronic schizophrenia with a stable medication in comparison to age and gender matched healthy adults. Every subject had to undergo a 6h fasting period before a newly developed, appetite-provoking fMRI task was applied. Subjects saw visual stimuli of appetitive food items in a 3Tesla scanner. In healthy controls food images elicited stronger activation in the striatum compared to SZ patients. When adjusting a ROI-based striatal activation for medication and weight, the group difference remained still significant. This points an effect of illness independent of antipsychotic medication. These data underscore the involvement of the striatum into salience attribution, reward anticipation and the neuronal pathways leading to altered eating behavior and weight gain in schizophrenia.
Abstract: Background: A deficit in Theory of mind (ToM) or ‘mentalizing’ has been purported to underlie the poor social functioning seen in patients with schizophrenia. To understand the neural basis of this deficit studies have primarily used tasks requiring ‘off-line’ or explicit mentalizing but, in daily life, successful social interactions depend upon implicit or ‘on-line’ mentalizing. Therefore in the present study we used functional neuroimaging and a task that elicits ‘on-line’ mentalizing to investigate the neural basis of ToM deficits in schizophrenia.Methods: Functional MRI images were acquired from 20 male patients with established schizophrenia and 19 age and gender matched healthy controls while they watched animated sequences involving two triangles. In the control condition the two triangles moved at random whereas in the experimental condition they moved interactively with implied intentions. The identification of ToM networks and differential responses between groups, within this network, was investigated using a random effects model. To account for differences in educational status between the groups this was included as a covariate in the between group analysis. Correlation analysis was performed to examine the relationship between neural activity change during mentalizing and the clinical and functional outcomes of patients.Results: Patients with schizophrenia had significantly diminished activity in the right superior temporal gyrus (STG) at the temporoparietal junction (TPJ) and bilaterally within the inferior frontal gyri (IFG). Interestingly, frontal neural activity showed significant correlation with functional outcomes in patients with schizophrenia.Conclusions: Findings from this novel study suggest that the ToM deficit in male schizophrenia patients may reflect impairment in the automatic or implicit processing of mentalizing. If replicated, this is an important finding that provides additional insight into the neural basis of impairments in social functioning that are experienced by patients with schizophrenia.
Abstract: Septum pellucidum (SP) and cavum SP (CSP) were delineated in two samples. The Longitudinal Study examined structural MR-images in first-episode schizophrenia (FESZ) and controls at two time-points. The Cross-Sectional Study examined structural and diffusion-tensor MR measures, including hippocampus and fornix, in chronic schizophrenia (SZ) at one time-point.CSP and SP measurements remained stable over time in FESZ and controls. Compared to controls, CSP were smaller in FESZ, but not in chronic SZ. SP were larger in chronic SZ, but not in FESZ. In chronic SZ only, SP-Length was correlated negatively with fornix-FA and hippocampal volume, and positively with chlorpromazine-equivalent dosage.
Abstract: Background: Social cognitive deficits contribute to functional disability in schizophrenia. Social cognitive tasks in healthy persons consistently evoke activation of medial prefrontal cortex, inferior frontal gyrus, temporoparietal gyrus, and posterior cingulate cortex/precuneus. We tested the hypothesis that patients with schizophrenia and their unaffected siblings share dysfunction of the same neural networks.Methods: Neural activation during emotion processing (EP), theory of mind (ToM), and control tasks was measured using functional magnetic resonance imaging (fMRI) in 14 patients with schizophrenia, 14 nonpsychotic siblings of patients with schizophrenia, and 14 matched healthy subjects.Results: Compared with healthy controls, patients with schizophrenia showed reduced activation of right hemisphere structures involved in EP and ToM including inferior frontal gyrus, middle frontal gyrus, and right temporoparietal junction. These deficits were shared, in part, by unaffected siblings. The latter group demonstrated deficits in bilateral precuneus activation during ToM, not present in patients.Conclusions: Schizophrenia appears to be associated with a deficit in activation of right hemisphere components of a ToM network. Such deficits are shared in part by those at high genetic risk but unaffected by schizophrenia.
Abstract: Background: Clozapine is widely prescribed for treatment refractory patients with schizophrenia, but its use is limited by potentially life threatening adverse effects. Rechallenge after these complications has been occasionally attempted in patients with severe psychotic symptoms.Objective: To review the outcome of clozapine rechallenge after potentially life threatening adverse effects.Methods: Electronic, all-language, literature search (1972–2011) followed by demographic and clinical data extraction. The outcome of rechallenge was considered favorable when the lower bound of the 95% confidence interval (CI) of the proportion of patients who could continue clozapine was >50%.Results: Altogether, 138 patients (mean age: 36.3years, 65.7% male, 57.6% Caucasian, virtually all with schizophrenia spectrum diagnosis) underwent clozapine rechallenge after developing neutropenia (n=112), agranulocytosis (n=15), neuroleptic malignant syndrome (NMS) (n=5), myocarditis (n=4), pericarditis (n=1) and lupus erythematosus (n=1). Rechallenge strategies were heterogeneous and not systematically evaluated. Clozapine rechallenge was successful in 78/112 patients (69.6%, CI: 60.6–77.4) after neutropenia, 3/15 (20%, CI: 7.1–45.2) after agranulocytosis, 5/5 (100%, CI: 56–100) after NMS, 3/4 (75%, CI: 30–95) after myocarditis, 1/1 after pericarditis, and 0/1 after clozapine-induced lupus. Successfully rechallenged patients were followed for 16–96weeks. None of the rechallenged patients died.Conclusions: Although controlled studies are clearly needed, using a priori, confidence interval-based criteria, case reports/series suggest that in refractory patients who benefited from clozapine, careful rechallenge can be considered after neutropenia and NMS, but not after agranulocytosis and myocarditis.
Abstract: Objective: The primary aim of this study was to compare the impact of risperidone long-acting injectable (R-LAI) to other antipsychotics on rates of hospitalisation in real-life settings.Method: The Cohort for the General study of Schizophrenia (CGS) followed 1859 patients diagnosed with schizophrenia (DSM-IV) from 177 psychiatric wards of public and private hospitals across France over a mean period of 12months. These patients were ambulatory or had been hospitalised for less than 93days at study entry. Recruitment was stratified for long-acting second-generation antipsychotic use. A multivariate Poisson regression adjusted for confounding with propensity scores and allowing for autocorrelation was used for the calculation of relative rates of hospitalisation with 95% confidence intervals.Results: The mean age of participants was 37.65years, 68.3% were male and 36.7% were hospitalised for less than 93days at study entry. Altogether, participants accumulated 796 hospital stays (53.4 per 100 person-years). R-LAI patients were slightly younger and had been hospitalised more often in the past 12months compared to non-R-LAI users. The adjusted Poisson regression analysis showed R-LAI use to be associated with a lower rate of future hospitalisation: 0.66 [0.46–0.96] compared to non-R-LAI use, and 0.53 [0.32–0.88] compared to use of other LAIs.Conclusion: Use of R-LAI was associated with lower rates of hospitalisation compared to non-use of R-LAI.
Abstract: Patients with schizophrenia who have predominant negative symptoms are often considered less responsive to treatment. This analysis of patients with schizophrenia or schizoaffective disorder compares changes in symptom severity between those with predominant versus merely prominent negative symptoms. Prominent negative symptoms were defined by a baseline score of ≥4 on at least 3, or ≥5 on at least 2, of the 7 Positive and Negative Syndrome Scale (PANSS) negative subscale items. Predominant negative symptoms were defined by the foregoing plus a PANSS positive score of <19, a Barnes Akathisia score of <2, a Simpson–Angus score of <4, and a Calgary Depressive Scale score of <9. Adult patients with schizophrenia (n=227) or schizoaffective disorder (n=116) received either olanzapine (10–20mg/day, n=169) or quetiapine (300–700mg/day, n=174) for up to 24weeks. Data for both medications were pooled. Of the 343 patients enrolled in the study, 34.7% met the criteria for predominant negative symptoms, the remaining 65.3% being characterized only by their prominent negative symptoms. Changes in the severity of negative symptoms in both patient types largely followed similar trajectories during treatment, as reflected both in Marder PANSS negative subscale scores and in the Scale for Assessment of Negative Symptoms total and domain scores. Patients with either predominant or prominent negative symptoms therefore appear to respond similarly to atypical antipsychotic treatment. This distinction, incorporating an evaluation of the presence of positive, affective, and extrapyramidal symptoms, may therefore not have prognostic implications for the responsiveness of patients' negative symptoms to treatment.
Abstract: Introduction: Reduced dopaminergic activity in the pre-frontal cortex may partially explain the negative symptoms of schizophrenia. Animal models have shown that adding an alpha-2 adrenergic receptor antagonist to a D2 antagonist can efflux dopamine into the frontal cortex increasing dopaminergic activity. Trials of alpha-2 antagonist add-on therapy in humans have been limited by small sample sizes. Therefore, a meta-analysis was conducted to determine if adding an alpha-2 antagonist to a D2 antagonist improves schizophrenia treatment by reducing negative symptoms.Methods: Randomized, placebo-controlled trials of the addition of an alpha-2 antagonist to a D2 antagonist were identified through a PubMed search. Treatment effects were measured using schizophrenia rating scales and meta-analyzed as standardized mean differences using random effects models.Results: Eight unique studies were identified, each including 18 to 41 patients and lasting four to eight weeks. The overall effect size of add-on alpha-2 therapy across the eight trials was an improvement of 0.16 (95% C.I., −.30 to 0.62) for positive symptoms, 0.84 (95% C.I., .17 to 1.51) for negative symptoms, 0.28 (95% C.I., −.08 to 0.64) for general symptoms, and .80 (95% C.I., .15 to 1.46) for symptoms overall. Negative symptom improvements were independent of improvements in depressive symptoms, measured using the Hamilton depression rating scale, for 3 of the 5 studies.Conclusions: Add-on agents with alpha-2 antagonist activity appear to improve the efficacy of D2 antagonists for the treatment of schizophrenia by reducing negative symptoms. These results support conducting a more definitive confirmatory clinical trial.
Abstract: Objective: To examine the effect of rimonabant on neurocognitive impairments in people with schizophrenia.Methods: Participants entered a 16-week double-blind, placebo-controlled, randomized clinical trial. A neurocognitive battery was administered at baseline and end of study.Results: In comparison to rimonabant (20mg/day), placebo-treated participants exhibited a significant improvement on the Repeatable Battery for the Assessment of Neuropsychological Status total score. In contrast, rimonabant was associated with significant improvement on a probabilistic learning task. There were no other significant treatment effects.Conclusions: Rimonabant did not improve global cognitive functioning, but did improve a specific learning deficit based on response to positive feedback.
Abstract: Antipsychotic drugs (APDs) are effective in treating some of the positive and negative symptoms of schizophrenia. APDs take time to achieve a therapeutic effect which suggests that changes in gene expression are involved in their efficacy. We hypothesized that there would be altered expression of specific genes associated with the etiology or treatment of schizophrenia in frontal cortex of rats that received chronic treatment with a typical APD (haloperidol) vs. an atypical APD (clozapine). Rats were administered clozapine, haloperidol, or sterile saline intraperitoneally daily for 21days. Frontal cortices from clozapine-, haloperidol-, and saline-treated rats were dissected and subjected to microarray analysis. We observed a significant (1.5 fold, p<0.05) downregulation of 278 genes and upregulation of 73 genes in the clozapine-treated brains vs. controls and downregulation of 451 genes and upregulation of 115 genes in the haloperidol-treated brains vs. control. A total of 146 genes (130 downregulated and 16 upregulated) were significantly altered by both clozapine and haloperidol. These genes were classified by functional groups. qRT-PCR (quantitative real-time polymerase chain reaction) analysis verified the direction and magnitude of change for a group of nine genes significantly altered by clozapine and 11 genes significantly altered by haloperidol. Three genes verified by qRT-PCR were altered by both drugs: Bcl2-like 1 (Bcl2l1), catechol-O-methyltransferase (Comt), and opioid-binding protein/cell adhesion molecule-like (Opcml). Our results show that clozapine and haloperidol cause changes in levels of many important genes that may be involved in etiology and treatment of schizophrenia.
Abstract: Objective: Antipsychotic treatment strategy for the maintenance phase of schizophrenia has been inconsistent in the literature. The purpose of this systematic review is to overview recommendations in various guidelines and algorithms.Methods: The guidelines and algorithms for schizophrenia that were published or updated in English after 2000 were searched, using Medline, PubMed, EMBASE, and PsycINFO with the following key words: guideline, algorithm, schizophrenia, and psychosis (last search: July 2011). The reference lists of the relevant reports were also examined.Results: Fourteen guidelines and algorithms were identified; only five of them clearly defined terms about the maintenance phase and treatment. Ten of 11 guidelines and algorithms did not recommend discontinuation of antipsychotics within five years; six of them partially recommended antipsychotic discontinuation for patients with first-episode schizophrenia exclusive. All nine guidelines and algorithms that referred to intermittent or targeted antipsychotic strategy endorsed against this strategy. Although being a hot topic of controversy, dose reduction of antipsychotics or lower dose therapy in the maintenance phase compared to the acute dosage is not recommended on the whole concerning atypical antipsychotics, whereas dose reduction appears sometimes considered acceptable for typical antipsychotics.Conclusion: What constitutes maintenance phase and its treatment in schizophrenia has not yet been established in the literature. While discontinuation and intermittent or targeted strategies are not generally recommended, there is controversy regarding dose reduction or lower dose therapy, especially with regards to atypical antipsychotics. Further evidence is needed in order to derive treatment recommendations on antipsychotics in this critical treatment phase of schizophrenia.
Abstract: Objective: The primary aim of this study was to compare electronic monitoring with other measures of adherence to antipsychotic medication in outpatients with schizophrenia. The secondary aim of the study was to analyze the relationships between adherence and other clinical parameters.Method: Fifty-one patients diagnosed with schizophrenia were monitored over an eight-week period. Medication adherence was assessed using the Medication Event Monitoring System (MEMS), which is a bottle cap with a microprocessor that records the occurrence and times of bottle opening, patient self-reports, a clinician rating scale, and pill counts. Agreements among adherence measures and the relationships between adherence and other clinical factors were assessed.Results: The rate of non-adherence according to the MEMS was 41.2%, considerably higher than those of pill counting (7.8%), clinician rating scale (7.8%), or self-reporting (25.5%). Excitement, impulse control, and preoccupation symptoms on the Positive and Negative Syndrome Scale (PANSS) were higher in the non-adherent patients than in the adherent patients. The full Drug Attitude Inventory (DAI) score was higher in adherent versus non-adherent patients and the significant other subscale of the Multidimensional Scale of Perceived Social Support score was lower in the adherent patients. The Clinical Global Impression-Severity score was negatively correlated with adherence as measured by the MEMS (r=−0.426, p<0.05) and DAI scores were positively correlated with adherence according to the MEMS and the clinician rating scale (r=0.498, p<0.01 and r=0.387, p<0.05). Multivariate analysis showed that PANSS and DAI scores significantly contributed to MEMS adherence.Conclusion: Adherence as measured by the MEMS showed a discrepancy with other measures of adherence in patients with schizophrenia. The severity of disease and attitudes toward medication were related to adherence. Further studies are needed to evaluate the impacts of medication adherence in schizophrenia.
Abstract: Background: Prepulse inhibition (PPI) of the startle response refers to the ability of a weak prestimulus to transiently inhibit the response to a closely following strong sensory stimulus. PPI provides an operational index of sensorimotor gating and is reduced, on average, in people with schizophrenia, relative to healthy people. Given the variable response to Cognitive Behaviour Therapy for psychosis (CBTp) and positive associations between pre-therapy brain and cognitive functions and CBT outcome across disorders, we examined whether pre-therapy level of PPI is associated with clinical outcome following CBTp.Method: Fifty-six outpatients stable on medication with at least one distressing symptom of schizophrenia and willing to receive CBTp in addition to their usual treatment were assessed on acoustic PPI. Subsequently, 28 patients received CBTp (CBTp+treatment-as-usual, 23 completers) for 6–8months and 28 continued with their treatment-as-usual (TAU-alone, 17 completers). Symptoms were assessed (blindly) at entry and follow-up.Results: The CBTp+TAU and TAU-alone groups did not differ demographically, clinically or in PPI at baseline. The CBTp+TAU group showed improved symptoms relative to the TAU-alone group, which showed no change, at follow-up. Pre-therapy PPI level correlated positively with post-CBTp symptom improvement.Conclusions: Relatively intact sensorimotor gating is associated with a good clinical response following a 6–8months course of NICE compliant CBTp in schizophrenia. Pharmacological or psychological interventions capable of improving PPI may enhance the effectiveness of CBTp in people with schizophrenia, particularly in those who fail to show clinical improvement with currently available antipsychotic drugs and adjunctive CBTp.
Abstract: Objectives: In earlier reports, growth-associated protein 43 (GAP-43) has been shown to be critical for initial establishment or reorganization of synaptic connections, a process thought to be disrupted in schizophrenia. Additionally, abnormal GAP-43 expression in different brain regions has been linked to this disorder in postmortem brain studies. In this study, we investigated the involvement of the gene encoding GAP-43 in the susceptibility to schizophrenia.Methods: We searched for genetic variants in the promoter region and 3 exons (including both UTR ends) of the GAP-43 gene using direct sequencing in a sample of patients with schizophrenia (n=586) and non-psychotic controls (n=576), both being Han Chinese from Taiwan, and conducted an association and functional study.Results: We identified 11 common polymorphisms in the GAP-43 gene. SNP and haplotype-based analyses displayed no associations with schizophrenia. Additionally, we identified 4 rare variants in 5 out of 586 patients, including 1 variant located at the promoter region (c.-258-4722G>T) and 1 synonymous (V110V) and 2 missense (G150R and P188L) variants located at exon 2. No rare variants were found in the control subjects. The results of the reporter gene assay demonstrated that the regulatory activity of construct containing c.-258-4722T was significantly lower as compared to the wild type construct (c.-258-4722G; p<0.001). In silico analysis also demonstrated the functional relevance of other rare variants.Conclusions: Our study lends support to the hypothesis of multiple rare mutations in schizophrenia, and it provides genetic clues that indicate the involvement of GAP-43 in this disorder.
Abstract: Background: Epidemiological studies indicate that having any family member with schizophrenia increases the risk of schizophrenia in the probands. However, genome-wide association studies (GWAS) have accounted for little of this variation. The aim of this study was to use a population-based sample to explore the influence of single-nucleotide polymorphisms (SNPs) on the excess schizophrenia risk in offspring of parents with a psychotic, bipolar affective or other psychiatric disorder.Method: A nested case–control study with 739 cases with schizophrenia and 800 controls. Their parents and siblings. Information from national health registers and GWAS data from the national neonatal biobank.Results: Offspring schizophrenia risk was elevated in those whose mother, father or siblings had been diagnosed with schizophrenia or related psychosis, bipolar affective disorder or any other psychiatric disorder. The rate ratio was 9.31 (3.85; 22.44) in offspring whose 1st degree relative was diagnosed with schizophrenia. This rate ranged between 8.31 and 11.34 when adjusted for each SNP individually and shrank to 8.23 (3.13; 21.64) when adjusted for 25% of the SNP-variation in candidate genes. The percentage of the excess risk associated with a family history of schizophrenia mediated through genome-wide SNP-variation ranged between −6.1%(−17.0%;2.6%) and 4.1%(−3.9%;15.2%). Analogous results were seen for each parent and for histories of bipolar affective and other psychiatric diagnoses.Conclusions: The excess risk of schizophrenia in offspring of parents who have a psychotic, bipolar affective or other psychiatric disorder is not currently explained by the SNP variation included in this study in accordance with findings from published genetic studies.
Abstract: Introduction: Small hippocampi and impaired memory are common in patients with psychosis and brain-derived neurotrophic factor (BDNF) plays a critical role in hippocampal neuroplasticity and memory. A common BDNF allele (Val66Met) has been the focus of numerous studies but results from the few BDNF-imaging studies are complex and contradictory. The objective of this study was to determine the association between Val66Met and hippocampal volume in patients with first episode psychosis. Secondary analyses explored age-related associations and the relationship between Val66Met and memory.Method: Hippocampal volume and BDNF genotyping were obtained for 58 patients with first-episode psychosis and 39 healthy volunteers. Patients were recruited from an early psychosis program serving a catchment-area population.Results: Hippocampal volume was significantly smaller in patients than controls (F1,92=4.03, p<0.05) and there was a significant group-by-allele interaction (F1,92=3.99, p<0.05). Hippocampal volume was significantly smaller in patients than controls who were Val-homozygotes but no group differences were found for Met carriers. Findings were not affected by diagnosis, antipsychotic medication, or age, and there was no change in hippocampal volume during a one-year follow-up. Val-homozygous patients had worse immediate and delayed memory than their Met counterparts.Conclusions: Results suggest the effects of the BDNF Val66Met allele may be different in patients with psychosis than in healthy adults. Hippocampal volume in patient and control Met allele carriers was very similar suggesting that illness-related factors have minimal influence in this group. In contrast, Val homozygosity was related to smaller hippocampi and poorer memory functioning only in patients with psychosis.
Abstract: Introduction: To improve the understanding of psychotic abnormalities and their non-Mendelian inheritance patterns, the epigenetic regulation of the psychotic disorder-associated GABRB2, gene for the type A γ-aminobutyric acid receptor β2-subunit, was investigated.Methods: Expression of GABRB2, and the epigenetic regulatory enzymes histone deacetylases (HDACs) and DNA methyltransferases (DNMTs) in mouse and postmortem human brains was analyzed using real-time PCR.Results: Results showed that expression of GABRB2 isoforms significantly increased over time in both mouse and human, especially for the long splicing isoform. In the brains of non-psychiatric controls (CON), a significant positive correlation of GABRB2 expression with age was observed in individuals with MM genotypes of the single nucleotide polymorphisms (SNPs) rs187269 and rs1816072. This was reversed to a significant negative correlation in schizophrenics (SCZ). A similar reversal was also displayed by bipolar disorder (BPD) patients. In parallel, a significant co-variation of HDAC1 with GABRB2 expression observed in CON remained significant in BPD but not in SCZ; comparably, a significant co-variation of HDAC2 with GABRB2 expression observed in CON became non-significant in both SCZ and BPD. Moreover, co-variations of DNMT1 and DNMT3B with GABRB2, not observable in CON, became significant in BPD.Conclusion: These findings demonstrated that GABRB2 expression was under epigenetic regulation that varied with development, genotype and disease status, and these regulatory mechanisms were observably disrupted in SCZ and BPD. This study provided insight into the complex inheritance patterns of psychiatric disorders, and pointed to the involvement of epigenetic dysregulation in the disease process of major psychotic disorders.
Abstract: The Wisconsin Schizotypy Scales (WSS) have been widely used in the study of clinical and non-clinical samples. However, researchers often find the length of the scales prohibitive. The present study examined the reliability and validity of recently developed 15-item short forms of the Perceptual Aberration, Magical Ideation, Physical Anhedonia, and Revised Social Anhedonia Scales in two large samples of non-clinically ascertained young adults. The scales demonstrated good reliability and correlated highly with the original scales. The validity of the scales was assessed by comparing the association of the original and shortened WSS with interview measures of psychotic-like and schizophrenia-spectrum symptoms and impaired functioning, as well as with questionnaire measures of personality and social impairment. The associations of the shortened WSS with the interview and questionnaire measures were comparable in terms of statistical significance and effect size with the associations of the original scales. The present findings provide the first demonstration of the validity of the shortened WSS and support their use in the study of schizotypy.
Abstract: Objective: Aggression, suicidality and involuntary treatment constitute severe clinical problems in first-episode psychosis (FEP). Although there are studies on prevalence and clinical predictors of these conditions, little is known on the influence of psychopathology and neuropsychological dysfunction.Method: 152 FEP inpatients were prospectively assessed using the Brief Psychiatric Rating Scale (BPRS) and a neuropsychological examination covering the domains ‘processing speed’, ‘concentration and attention’, ‘executive function’, ‘working memory’, ‘verbal memory’, ‘verbal comprehension’, ‘logical reasoning’, ‘global cognition’, and ‘general intelligence’. Clinical data were collected retrospectively in a structured file audit trial.Results: Patients were aged 24.5±4.9years, and 112 (74%) were male. At admission, 13 (9%) patients presented with severe aggression, and 28 (18%) with severe suicidality. 31 patients (20%) received involuntary treatment. In multivariate analyses, aggression was predicted by BPRS-Excited Component (BPRS-EC; p=.001), suicidality was predicted by BPRS-EC (p=.013) and general intelligence (p=.016), and predictors for involuntary treatment were BPRS-EC (p=.001) and neuropsychological dysfunction in the domain ‘concentration and attention’ (p=.016).Conclusion: Psychopathology and neuropsychological functioning independently predict dangerous behavior in FEP patients. Some correlations with neuropsychology (e.g., of aggression with concentration/attention) are absent in multivariate analyses and may thus constitute a proxy of psychopathological features. In addition to clinical data, BPRS-EC can be used as a predictor of dangerous behavior. Patients with severe aggression and suicidality show different patterns of neuropsychological dysfunction, indicating that suicidality should not be conceptualized as subtype of aggressive behavior.
Abstract: The MATRICS Consensus Cognitive Battery (MCCB), developed by the National Institute of Mental Health (NIMH) Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) initiative, has been recommended as the standard battery for clinical trials of cognition-enhancing interventions for schizophrenia. Normative data for the MCCB has been previously obtained in the U.S. Extrapolation of these normative data to different countries may be problematic due to the translation of the different tests, as well as potential cultural influences. We present the process of obtaining normative data for the MCCB in Spain with administration of the battery to a general community standardization sample. In addition, we examine the influence of age, gender, and educational level on test performance. The MCCB was administered to a total sample of 210 healthy volunteers, at three Spanish sites. For each site, recruitment of the sample was stratified according to age, gender, and educational level. Our findings indicate significant age, gender, and education effects on the normative data for the MCCB in Spain, which are comparable to those effects described for the original standardized English version in the U.S. The fact that the normative data are comparable, and that the variables age, gender, and education have a similar influence on performance, supports the robustness of the MCCB for use in different countries.
Auditory verbal hallucinations (AVH) are a core symptom of schizophrenia and related spectrum-disorders. So far, magnetic resonance imaging (MRI) has been employed to study the functional neuroanatomy of AVH using two distinct methods, either by capturing symptoms during the actively hallucinating state or by investigating neural responses during explicit cognitive processing (). Both approaches, however, face certain limitations. For instance, the self-identification of AVH is accompanied by the cognitive and motor response associated with this event, together with increased self-awareness. This interaction might change the participant’s subjective experience and quality of the hallucinatory symptom. On the other hand, interactions between experimental stimuli and symptoms could drive activation patterns that may not represent the “pure” neural substrate of AVH. In this study, we investigated the neural correlates at rest of AVH in schizophrenia using an MRI-based technique of perfusion imaging using continuous arterial spin labelling [CASL] (). The objectives of our study were threefold: first, we tested the hypothesis that patients with schizophrenia with treatment-refractory AVH would exhibit symptom-related perfusion changes within a speech-related network, as predicted by AVH models of dysfunctional speech generation and misattribution (). Second, we investigated the symptom-specificity of brain perfusion abnormalities in AVH patients by including a group of non-hallucinating schizophrenic patients. Third, we explored the relationship between regional cerebral blood flow (rCBF) and multiple dimensions of AVH, as assessed by symptom-specific psychometrics.
Dear Editors, In schizophrenia, there is strong evidence for familiality of age at onset (AAO) (), suggested by genetic linkage to specific chromosomal regions ().
Dear Editors, Several studies reviewed elsewhere (), described reduction of pulvinar volume and/or neuronal number in schizophrenia (SZ) but there were discrepancies regarding the laterality of the effects and the exact pulvinar divisions most altered. We examined neuronal and oligodendrocyte number in the medial division of the pulvinar (PM) of specimens from subjects with SZ and nonpsychiatric controls (NC), employing Nissl-stained sections from the Stanley Foundation Brain Collection in which some specimens are from the right hemisphere and others from the left (). Demographics and tissue processing are fully described elsewhere (), as is our delineation of PM (). Stereo Investigator 9 software (MBF Bioscience, Williston VT) was employed to implement the optical fractionator design () for estimating neuronal and oligodendrocyte numbers. Statistical methods were similar to those used previously ().
