Is the P300 wave an endophenotype for schizophrenia? A meta-analysis and a family study

INTRODUCTION: We assessed the usefulness of the P300 wave as endophenotype for schizophrenia by means of a meta-analysis of the literature as well as our own family study. METHOD: Meta-analysis: We conducted a systematic search for articles published between 1983 and 2003 that reported P300 measures in non-psychotic relatives of schizophrenic patients and in healthy controls. Meta-regression analyses were performed using a random effects procedure. The pooled standardized effect size (PSES) was calculated as the difference between the means of the two groups divided by the common standard deviation. Local study: We examined the P300 wave with a standard two-tone oddball paradigm in 30 patients with schizophrenia, 40 non-psychotic relatives, and 40 controls using linear mixed models. RESULTS: Meta-analysis: We pooled 472 relatives and 513 controls. The P300 amplitude was significantly reduced in relatives (PSES = 0.61; 95% CI: 0.30 to 0.91; P < 0.001). The P300 latency was significantly delayed in relatives (PSES of -0.50; 95% CI: -0.88 to -0.13; P = 0.009]. Local study: The patients showed a trend for amplitude reductions (P = 0.06) and significant latency delays (P < 0.01). The relatives displayed normal amplitude but had significant latency delays (P = 0.01). The P300 amplitude and especially the P300 latency are promising alternative phenotypes for genetic research into schizophrenia.     

Impaired response inhibition and excess cortical thickness as candidate endophenotypes for trichotillomania

Trichotillomania is characterized by repetitive pulling out of one's own hair. Impaired response inhibition has been identified in patients with trichotillomania, along with gray matter density changes in distributed neural regions including frontal cortex. The objective of this study was to evaluate impaired response inhibition and abnormal cortical morphology as candidate endophenotypes for the disorder. Subjects with trichotillomania (N = 12), unaffected first-degree relatives of these patients (N = 10), and healthy controls (N = 14), completed the Stop Signal Task (SST), a measure of response inhibition, and structural magnetic resonance imaging scans. Group differences in SST performance and cortical thickness were explored using permutation testing. Groups differed significantly in response inhibition, with patients demonstrating impaired performance versus controls, and relatives occupying an intermediate position. Permutation cluster analysis revealed significant excesses of cortical thickness in patients and their relatives compared to controls, in right inferior/middle frontal gyri (Brodmann Area, BA 47 & 11), right lingual gyrus (BA 18), left superior temporal cortex (BA 21), and left precuneus (BA 7). No significant differences emerged between groups for striatum or cerebellar volumes. Impaired response inhibition and an excess of cortical thickness in neural regions germane to inhibitory control, and action monitoring, represent vulnerability markers for trichotillomania. Future work should explore genetic and environmental associations with these biological markers.     

Psychosis-proneness correlates with expression levels of dopaminergic genes

Psychosis-proneness or schizotypy is a personality organisation mirroring individual risk for schizophrenia-development. Believed to be a fully dimensional construct sharing considerable geno- and phenotypal variance with clinical schizophrenia, it has become an increasingly promising tool for basic psychosis-research. Although many studies show genetic commonalities between schizotypy and schizophrenia, changes in regulation of gene expression have never been examined in schizotypy before. We therefore extracted RNA from the blood, a valid surrogate for brain tissue, of a large sample of 67 healthy male volunteers and correlated the activities of all genes relevant for dopaminergic neurotransmission with the positive schizotypy-scale of the O-LIFE. We found significant negative correlations regarding the expression of the genes COMT, MAOB, DRD4, DRD5 and FOS, indicating that increased schizotypy coincides with higher levels of dopaminergic dysregulation on the mRNA-level. Considering the advantages of this method, we suggest that it be applied more often in fundamental psychosis-research.     

精神分裂症首次发病患者及其健康同胞认知功能的比较研究

目的 比较精神分裂症首次发病患者与健康同胞及正常对照认知功能的差异,探讨精神分裂症在认知功能领域的内表型.方法 采用目前常用的范畴流畅测验(CFT)、数字符号编码测验(DSCT)、连线测验(TMT)、韦克斯勒记忆量表第3版(WMS-Ⅲ)空间广度测验(WMS-ⅢSST)、霍普金斯词汇学习测验-修订版(HVLT-R)、简易视觉空间记忆测验-修订版(BVMT-R)、定步调听觉连续加法测验(PASAT)和威斯康星卡片分类测验-64(WCST-64)对92例精神分裂症首次发病患者(患者组)、56例健康同胞(同胞组)和62名健康对照者(对照组)的认知功能进行检测.结果 (1)患者组所有神经心理测验成绩均差于对照组,差异有统计学意义(P＜0.01).(2)同胞组的CFT、DSCT、TMT、HVLT-R即刻记忆和延迟记忆、BVMT-R即刻记忆、PASAT、WCST-64持续错误数、持续反应数和完成分类数的测验成绩差于对照组,差异有统计学意义(P＜0.05).(3)患者组与同胞组的CFT、WCST-64中的持续错误数、持续反应数和完成分类数测验成绩分别为(18.40±12.12)分比( 18.86±5.19)分、(16.48±8.19)分比(14.80±5.86)分、(18.76±10.91)分比(16.86 ±7.73)分、(1.33±2.81)分比(1.63±1.36)分,2组比较差异无统计学意义(P＞0.05),其他神经心理测验成绩比较,患者组差于同胞组,差异有统计学意义(P＜0.05).结论 精神分裂症首次发病患者存在处理速度、工作记忆、言语记忆、空间记忆、注意警觉和执行功能广泛性的认知功能损害,精神分裂症健康同胞存在处理速度、言语记忆、视觉记忆、注意警觉、执行功能的认知缺陷;语义流畅性功能和执行功能可能是精神分裂症的潜在内表型.     

Dimensional endophenotypes in bipolar disorder: Affective dysregulation and psychosis proneness

Background

The clinical phenotype of bipolar disorder (BPD) is heterogeneous and the genetic architecture of the disorder is complex and not well understood. Given these complications, it is possible that the identification of intermediate phenotypes (“endophenotypes”) will be useful in elucidating the complex genetic mechanisms that result in the disorder. The examination of unaffected relatives is critical in determining whether a particular trait is genetically-relevant to BPD. However, few dimensional traits related to BPD have been assessed in unaffected relatives of patients.

Methods

We assessed affective temperament and schizotypy in 55 discordant sibling pairs and 113 healthy controls (HCs) using the Temperament Evaluation of Memphis, Pisa, Paris, and San Diego, Auto-questionnaire version (TEMPS-A) to assess affective temperament and the Schizotypal Personality Questionnaire (SPQ) to assess schizotypy.

Results

BPD patients scored significantly higher than HCs on all subscales of the SPQ and on all but one subscale (hyperthymic) of the TEMPS-A (all p<0.01). Siblings demonstrated scores that were significantly intermediate to patients and HCs on the anxious subscale of the TEMPS-A and on the interpersonal deficits and disorganized subscales of the SPQ.

Limitations

We did not investigate the BPD spectrum as most patients were diagnosed with BPD I (n=47). Most of the patients had experienced psychosis (n=42) and so we were unable to examine whether psychosis status impacted upon affective temperament or schizotypy in patients or their siblings.

Conclusion

These data suggest that schizotypy and affective temperament represent dimensional traits that are likely to underlie the genetic risk for BPD.     

The effect of red light on backward masking in individuals with psychometrically defined schizotypy

Introduction. Previous research has suggested that individuals with schizophrenia and their relatives show a change in backward masking performance with a red background that is in the opposite qualitative direction as that found in nonpsychiatric controls. The present study examines this effect in individuals with psychometrically defined schizotypy to explore the potential of this effect to be a useful new qualitative endophenotype for schizophrenia-spectrum traits.

Methods. The Abbreviated Youth Psychosis At-Risk Questionnaire was used to screen a large number of undergraduates for schizotypy symptoms. A sample of 23 participants scoring high on this measure were compared to a sample of 26 controls on a location backward masking task that was presented on both red and green backgrounds.

Results. Consistent with findings in patients with schizophrenia, the participants reporting a high number of schizotypy features showed a decrease in performance to the red (compared to green) background and the controls showed a nonsignificant increase in performance—although this finding was limited to the stimulus–onset asynchrony (SOA) value that approximated the SOA with the largest effect size in the previous schizophrenia study (69 ms).

Conclusions. Although limited to one SOA, results extend earlier findings approximating this SOA to include a psychometrically defined schizotypy sample.     

A review of selected candidate endophenotypes for depression

Endophenotypes are proposed to occupy an intermediate position in the pathway between genotype and phenotype in genetically complex disorders such as depression. To be considered an endophenotype, a construct must meet a set of criteria proposed by Gottesman and Gould (2003). In this qualitative review, we summarize evidence for each criterion for several putative endophenotypes for depression: neuroticism, morning cortisol, frontal asymmetry of cortical electrical activity, reward learning, and biases of attention and memory. Our review indicates that while there is strong support for some depression endophenotypes, other putative endophenotypes lack data or have inconsistent findings for core criteria.     

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.