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.     

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.     

Mood and metabolic consequences of sleep deprivation as a potential endophenotype’ in bipolar disorder

It has been commonly recognized that circadian rhythm and sleep/wake cycle are causally involved in bipolar disorder. There has been a paucity of systematic research considering the relations between sleep and mood states in bipolar disorder. The current study examines the possible influences of sleep deprivation on mood states and endocrine functions among first-degree relatives of patients with bipolar disorder and healthy controls. Blood samples were taken at two time points in the consecutive mornings at predeprivation and postdeprivation periods. Participants simultaneously completed the Profiles of Mood States at two time points after giving blood samples. Plasma T3 and TSH levels increased after total sleep deprivation in both groups. Sleep deprivation induced TSH levels were reversely associated with depression–dejection among healthy controls. A paradoxical effect was detected for only the first-degree relatives of the patients that changes in plasma cortisol levels negatively linked to depression–dejection and anger–hostility scores after total sleep deprivation. Plasma DHEA levels became correlated with vigor-activity scores after sleep deprivation among first-degree relatives of bipolar patients. On the contrary, significant associations of depression–dejection, anger–hostility, and confusion–bewilderment with the baseline plasma DHEA levels became statistically trivial in the postdeprivation period. Findings suggested that first-degree relatives of patients with bipolar disorder had completely distinct characteristics with respect to sleep deprivation induced responses in terms of associations between endocrine functions and mood states as compared to individuals whose relatives had no psychiatric problems. Considering the relationships between endocrine functions and mood states among relatives of the patients, it appears like sleep deprivation changes the receptor sensitivity which probably plays a pivotal role on mood outcomes among the first-degree relatives of patients with bipolar disorder.     

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.     

Patterns of gaze behavior during an eye-tracking measure of joint attention in typically developing children and children with autism spectrum disorder

This study evaluated whether diagnostic classifications or features of ASD were associated with individual differences in children's gaze pattern during an eye-tracking measure of joint attention. The sample included 21 children with ASD (mean age, 7.3 ± 1.5 years) and 24 typically developing children (mean age, 6.8 ± 1.6 years), matched on receptive language abilities. Results revealed no significant group differences on global measures of gaze allocation (total gaze time allocation). However, significant group differences emerged using a measure evaluating a microstructure of children's gaze (duration of first fixation). In addition, individual differences in children's gaze pattern were reliably predicted by parent report measures of children's social abilities. The majority of children in this sample (including all typically developing children and those children with ASD who scored lowest on the SRS Social Awareness subscale) showed significant modulation in eye-gaze between the two experimental conditions. In contrast, children with ASD who also scored the highest on the SRS Social Awareness subscale consistently failed to modulate their eye gaze in accordance with the experimental condition. This failure to flexibly modulate gaze in the context of a joint attention eye-tracking paradigm may reveal children's limited awareness of social cues that may further limit social learning.     

Schizophrenia-like neurophysiological abnormalities in 22q11.2 deletion syndrome and their association to COMT and PRODH genotypes

22q11.2 deletion syndrome (22q11.2DS) is a common genetic risk factor for the development of schizophrenia. We investigated two neurophysiological endophenotypes of schizophrenia – P50 sensory gating and mismatch negativity in 22q11.2DS subject and evaluated their association with catechol O-methyltransferase (COMT) and proline dehydrogenase (PRODH) genetic variants. We also assessed the association of neurophysiological measures with schizophrenia-like symptomatology in 22q11.2DS. Fifty-nine subjects, 41 with 22q11.2DS and 18 typically developing controls, participated in the study. The participants with 22q11.2DS were genotyped for the COMT Val¹⁵⁸Met (rs4680) and PRODH Gln¹⁹Pro (rs2008720) and Arg¹⁸⁵Trp (rs4819756) polymorphisms. Following psychiatric evaluation, all the participants underwent neurophysiological recordings and executive function assessment. The 22q11.2DS group showed poorer sensory gating of the P50 response than the controls. Within the 22q11.2DS group, the COMT Met allele was associated with poorer sensory gating, while both the COMT Met allele and the PRODH Pro-Arg haplotype were associated with smaller mismatch negativity amplitudes. Smaller mismatch negativity amplitudes predicted greater impairment of executive functions and greater severity of schizophrenia-like negative symptoms in 22q11.2DS. The current study demonstrates that sensory gating impairments that are typical of schizophrenia are found in 22q11.2DS subjects. Our results further suggest that COMT and PRODH genetic variations contribute to sensory gating and mismatch negativity schizophrenia-like impairments in 22q11.2DS, possibly via dopaminergic/glutamatergic networks. The associations of mismatch negativity impairments with increased severity of schizophrenia-like negative symptoms and poorer executive functions performance in our 22q11.2DS sample suggest that mismatch negativity is a potential endophenotype for schizophrenia in 22q11.2DS.     

An examination of associations between the inability to taste phenylthiocarbamide (PTC) and clinical characteristics and trait markers in first-episode,nonaffective psychotic disorders

Research findings are mixed as to whether or not the inability to taste phenylthiocarbamide (PTC) might represent an endophenotypic trait marker for schizophrenia. We hypothesized associations between PTC-tasting status and select clinical characteristics and trait markers in patients with psychotic disorders that, if present, would provide support for the inability to taste PTC as a trait marker. In a first-episode psychosis sample (n=93), we measured PTC tasting, family history of psychosis, age at onset of prodrome and psychosis, severity of positive and negative symptoms, global impairment in functioning, neurological soft signs, and four neurocognitive domains (verbal learning/memory, visual learning/memory, verbal working memory, and spatial working memory). Associations between PTC-non-tasting and clinical/neurocognitive variables were examined with χ² tests and independent samples t tests. Among participants, 67.7% tasted PTC in comparison to a strip of control paper, and 25.8% were non-tasters. Tasters and non-tasters did not show statistically significant differences with respect to family history, age at onset, severity of symptoms, neurological soft signs, or the four neurocognitive domains. In conjunction with other findings, it is unlikely that PTC-non-tasting is a trait marker of schizophrenia, though a conclusive study is warranted.     

The relation between frontal EEG asymmetry and the risk for anxiety and depression

Frontal asymmetry of EEG alpha power (FA) may index the risk for anxiety and depression. Evidence linking FA to the underlying biological mechanisms is scarce. This is unfortunate because FA has potential as a biological marker to support gene finding in anxiety and depression. We examined the heritability of FA in 732 twins and their singleton siblings, and established the genetic and environmental contribution to the relation between FA and the risk for anxiety and depression. Multivariate models showed that FA is heritable only in young adults (males 32% and females 37%) but not in middle-aged adults. A significant relation between FA and the risk for anxiety and depression was only found in young adult females. This relation was explained by shared genes influencing both EEG and disease risk. Future studies on asymmetry of left and right frontal brain activation should carefully consider the effects of sex and age.