Cognitive event-related potentials differentiate schizophrenia with obsessive-compulsive disorder (schizo-OCD) from OCD and schizophrenia without OC symptoms

Clinical and neurobiological evidence suggests that concurrent presentation of schizophrenia and obsessive–compulsive (schizo-OCD) symptoms represents a distinct clinical entity. Given that obsessive-compulsive disorder (OCD) and schizophrenia have been modeled as having different neurofunctional profiles, the overlap between them represents a heuristic challenge for cognitive and endophenotype research. Event-related potentials (ERPs) may be used to probe neurophysiological correlates of the cognitive, emotional and behavioral disturbances found in neuropsychiatric entities such as schizo-OCD. Here we measure ERPs during a discriminative response task (DRT) in patients presenting with the DSM-IV criteria for both schizophrenia and OCD. We also performed these measurements in patients with OCD without psychotic features, as well as in patients with schizophrenia without OC symptoms. Schizo-OCD patients showed a distinct ERP pattern, with abnormally increased target activation (akin to OCD patients, but unlike the pattern observed in schizophrenic patients) and reduced P300 amplitudes (akin to schizophrenic patients, but unlike OCD patients). Similar to the control subjects, schizo-OCD patients showed larger amplitudes in the non-target condition than in the target condition. These results suggest that schizo-OCD may not only be a distinct clinical entity from pure OCD and schizophrenia, but it may also be characterized by a distinguishable neurophysiologic pattern. Neurobiological underpinnings deserve further considerations and might drive to a definition of a distinctive endophenotype for schizo-OCD in the de-construction of the schizophrenia endophenotype.     

Genome-wide expression analysis of peripheral blood identifies candidate biomarkers for schizophrenia

The aim of this study was to analyze gene expression in blood of patients with newly-diagnosed schizophrenia during their first psychotic episode and subsequent remission. Whole blood samples were obtained from 32 untreated patients presenting with their first psychotic episode suggestive of schizophrenia and 32 age- and gender-matched controls. Using Affymetrix micoarrays, we identified significantly altered expression of 180 gene probes in psychotic patients compared to controls. A subset of four significantly changed genes was further confirmed with QRT-PCR. The following genes were significantly altered in patients: glucose transporter, SLC2A3 (p < 0.001) and actin assembly factor DAAM2 (p < 0.001) were increased, whereas translation, zinc metallopeptidase, neurolysin 1 and myosin C were significantly decreased (p < 0.05). Expression of these candidate markers was also analyzed in a longitudinal study (12-24 months) in 12 patients who achieved full remission. Interestingly, expression of DAAM2 returned to control levels in patients who were in remission after their first psychotic episode, suggesting that its expression correlates with diseases progression and/or response to treatment. In summary, we identified changes of gene expression from peripheral blood which might help discriminate patients with schizophrenia from controls. While these results are promising, especially for DAAM2 whose polymorphic variants have been found significantly associated with schizophrenia, it will be important to analyze larger cohorts of patients in order to firmly establish changes in gene expression as blood markers of schizophrenia.     

Expression of hippocampal brain-derived neurotrophic factor and its receptors in Stanley consortium brains

Several lines of evidence implicate BDNF in the pathophysiology of psychiatric illness. BDNF polymorphisms have also been associated with the risk of schizophrenia and mood disorders. We therefore investigated whether levels of (pro)BDNF and receptor proteins, TrkB and p75, are altered in hippocampus in schizophrenia and mood disorder and whether polymorphisms in each gene influenced protein expression. Formalin-fixed paraffin-embedded hippocampal sections from subjects with schizophrenia, major depressive disorder (MDD), bipolar disorder (BPD) and non-psychiatric controls were obtained from the Stanley Foundation Neuropathology Consortium. (pro)BDNF, TrkB(T1) and p75 protein densities were quantified by immunoautoradiography and DNA extracted from each subject was used to determine the effect of genotype on protein expression. In MDD, reductions in (pro)BDNF were seen in all layers of the right but not the left hippocampus with no changes in the dentate gyrus. The pattern was similar but less marked for BPD. In addition, BPD but not MDD patients, had bilateral reductions in p75 in hippocampal layers but not in dentate gyrus. No changes in TrkB(T1) density were seen in any diagnosis. These findings suggest MDD and BPD may share impairment in (pro)BDNF expression. However, BPD may involve impairments of both (pro)BDNF and p75 receptor, whereas MDD may involve impaired (pro)BDNF alone. Moreover, the lateralisation of changes may indicate a role of asymmetry in vulnerability to MDD. Hippocampal (pro)BDNF and receptor levels were also affected by genotype, suggesting that allelic variations are important in the hippocampal abnormalities seen in these psychiatric disorders.     

Inefficient neural activity in patients with schizophrenia and nonpsychotic relatives of schizophrenic patients: Evidence from a working memory task

Studies of schizophrenia with functional MRI have shown hyper- and hypoactivations in various brain regions including the prefrontal cortex. Functional anomalies have also been reported in first-degree relatives of schizophrenic patients. The aim of this study was to examine working memory related brain functions in healthy subjects, schizophrenic patients and unaffected relatives and to determine the influence of psychopathology on these processes. A parametric n-back working memory task and functional MRI were used to examine 61 patients with schizophrenia, 11 nonpsychotic relatives of schizophrenic patients and a comparison group of 61 healthy subjects. The results indicated increased as well as decreased brain functions in schizophrenic patients compared to the control group depending on the task difficulty and the performance: during the attention task (0-back), which served as control condition, behavioral responses of patients and healthy subjects hardly differed but BOLD responses were considerably enhanced in schizophrenic patients. With increasing task difficulty differences between groups in BOLD responses diminished whereas behavioral deficits of patients increased. The examination of attention-independent working memory-functions (2- vs. 0-back) produced hypoactivations in patients, especially in frontal, temporal and subcortical brain regions. Furthermore, positive symptoms were associated with parietal dysfunctions. Behavioral performance and neural responses of unaffected relatives of schizophrenic patients were intermediate between schizophrenic patients and controls indicating slight brain dysfunctions. In addition, compensatory strategies were demonstrated. These findings suggest that the genetic risk for schizophrenia is accompanied by neural inefficiency which is associated with cognitive deficits, especially in difficult tasks.     

Employment Discrimination Against Schizophrenia

This paper addresses the issue of employment discrimination against individuals with a history of schizophrenia. There are three illustrations, two of which come from Asian countries, where the discrimination tends to be more openly expressed than in the West. Maintaining competitive employment is crucially important for individuals who are recovering from schizophrenia; indeed, employment is an inherent part of recovery. The paper makes recommendations for clinicians, advocates, patients, and employers.     

Abnormal timing of visual feedback processing in young adults with schizophrenia

Background

Recent studies have shown that schizophrenia is characterized by visual perceptual deficits, especially in the ability to integrate stimulus details into a global percept. Also, several studies have found amplitude attenuation of the visual P1 component of the event-related brain potential (ERP), probably indicating impaired visual feedforward processing in schizophrenia. However, there is little knowledge on the role of feedbackward processing in this group. This question is of importance, as recent studies indicate that feedback processing is critical in stimulus integration.

Methods

In the present study we tested whether there is evidence for atypical recurrent processing in a group of 14 young adults with recent-onset schizophrenia (mean age 21.7 years, mean TIQ 92.7) and 17 age and IQ matched control subjects, all males. To achieve this aim, we used a texture segregation task and measured ERP activity concurrently.

Results

We found normal amplitudes, but longer latencies of activity related to feedbackward processing in the schizophrenia group. In addition, we found enhanced occipito-temporal activity around 160 ms that is probably the reflection of increased detail processing.

Discussion

We show for the first time evidence for abnormal timing in feedback activity related to visual perception in subjects with schizophrenia. It is hypothesized that this latency effect is the functional reflection of abnormal structural connectivity in this group, and might result in increased processing of stimulus detail.     

Higher BDNF concentrations in the hippocampus and cortex of an aggressive mouse strain

Chronic psychosocial stress has been suggested as “second hit” in the etiology of neuropsychiatric disease, but experimental evidence is scarce. We employed repetitive social defeat stress in juvenile mice, housed individually or in groups, and measured sensorimotor gating by pre-pulse inhibition (PPI), a marker of neuronal network function. Using the resident-intruder paradigm, 28-day old C57BL/6NCrl mice were subjected daily for 3 weeks to social defeat. PPI and basic behaviour were analyzed 10 weeks later. Whereas stress increased the level of anxiety in all animals, persistent PPI deficits were found only in individually housed mice. Thus, social support in situations of severe psychosocial stress may prevent lasting impairment in basic information processing.     

No association of serotonin transporter polymorphism (5-HTTVNTR and 5-HTTLPR) with characteristics and treatment response to atypical antipsychotic agents in schizophrenic patients

Background

Serotonin transporter is a candidate gene for the pathogenesis of some psychiatric disorders. The aim of this study was to examine the role of the serotonin transporter gene polymorphism in the clinical aspects of schizophrenia including symptomatology and therapeutic response.

Methods

This study comprised 141 unrelated patients who strictly met the DSM-IV criteria for schizophrenia and 115 control subjects. All subjects were of Korean ethnicity. Serotonin transporter intron 2 VNTR polymorphism (5-HTTVNTR) and serotonin transporter linked polymorphic region polymorphism (5-HTTLPR) were analyzed in schizophrenia patients and control subjects. The Positive and Negative Symptom Scale (PANSS) was used at baseline and 6 weeks after atypical antipsychotic treatment to evaluate the clinical symptoms. Body mass index (BMI), the Barnes Akathisia Rating Scale (BARS), the Simpson–Angus Rating Scale (EPS) for adverse effect and the Calgary Depression rating Scale for Schizophrenia (CDSS) were measured.

Results

There were no significant differences in the frequency of genotypes between schizophrenia patients and control subjects. There were no significant differences in PANSS scores before treatment according to the serotonin transporter genotypes. Treatment response after atypical antipsychotics did not differ among the genotypes. No difference was shown among the genotypes for the scales in adverse effects and depression (BMI, BARS, EPS, CDSS).

Conclusions

Our results suggest that the serotonin transporter polymorphism does not seem to be a susceptibility factor for schizophrenia. Similarly, the serotonin transporter polymorphism might not affect the therapeutic response and adverse effect to atypical antipsychotics in Korean patients with schizophrenia. Further studies with a larger number of subjects are required to better understand the role of the serotonin transporter polymorphism in schizophrenia.     

Brain volume and dysexecutive behavior in schizophrenia

Objective

Behaviors associated with frontal/executive impairments are common in patients with schizophrenia. Our aim was to reconfirm that morphological brain abnormalities in schizophrenia patients would overlap the areas underpinning frontal systems behavior, and examine whether any specific association exists between abnormalities of brain structures and frontal behavioral deficits in schizophrenia patients.

Method

Twenty-six schizophrenia patients and 26 matched healthy controls underwent structural magnetic resonance imaging and their frontal function was assessed by a self-rating questionnaire, Frontal Systems Behavior Scale (FrSBe). We applied voxel-based morphometry (VBM) to investigate regional brain volume alternations.

Result

Compared with healthy controls, schizophrenia patients showed reduced gray matter volume in multiple frontal and temporal structures, namely, the bilateral dorsolateral prefrontal cortices (DLPFC), bilateral medial prefrontal cortices, left ventrolateral prefrontal cortex, bilateral anterior cingulate cortices, and bilateral superior temporal gyri. The scores on the executive dysfunction subscale of the FrSBe were correlated with volume reduction in the bilateral DLPFC in the patient group.

Conclusion

Our result suggests that pathology of the DLPFC could be the neural basis of real-life dysexecutive behaviors in schizophrenia patients.     

Do schizophrenia and bipolar disorders share a common disease susceptibility variant at the MMP3 gene?

There is growing evidence of partial etiological overlap between schizophrenia (SZ) and bipolar I disorder (BD-I) from linkage analysis, genetic epidemiology and molecular genetics studies. SZ and BD-I are neurodevelopmental disorders with genetic and environmental etiologies. Recent studies have demonstrated that matrix metalloproteinase 3 (MMP3) is a key event in associative memory formation, learning and synaptic plasticity, which are important in psychiatric disorders. In the light of these findings, we analyzed the genetic variations in the MMP3-1171 5A/6A in patients with SZ, patients with BD-I and healthy controls. To the best of our knowledge, this is the first study to report an association of variation in gene encoding MMP3 with SZ. Our study group consisted of 111 unrelated patients with SZ, 141 unrelated patients with BD-I, and 121 unrelated healthy controls. The frequencies of 6A6A genotype and 6A allele distributions of MMP3 in patients with SZ were significantly decreased when compared with controls. In contrast, in patients with SZ, the distributions of 5A5A genotype and 5A allele of MMP3 gene were significantly increased as compared with healthy controls. When the frequencies of genotypes or alleles in schizophrenic patients and bipolar patients were compared, 6A6A genotype and 6A allele in patients with BD-I were significantly higher than patients with SZ. In contrast, 5A5A genotype and 5A allele distributions of MMP3 gene were significantly frequent in patients with SZ. On the other hand, no significant differences were found in the allele or genotype distribution in patients with BD-I compared with controls. In conclusion, our data have supported the hypothesis that there is a possible relationship between − 1171 5A/6A polymorphism of MMP3 gene and SZ. A larger sample group is needed to confirm the potential role of this gene in the pathophysiology of psychiatric disorders.