Endophenotypic Marker For Schizophrenia Research Articles

Executive Control and Associated Brain Activity in Children With Familial High-Risk of Schizophrenia or Bipolar Disorder: A Danish Register-based Study.

Impaired executive control is a potential prognostic and endophenotypic marker of schizophrenia (SZ) and bipolar disorder (BP). Assessing children with familial high-risk (FHR) of SZ or BP enables characterization of early risk markers and we hypothesize that they express impaired executive control as well as aberrant brain activation compared to population-based control (PBC) children. Using a flanker task, we examined executive control together with functional magnetic resonance imaging (fMRI) in 11- to 12-year-old children with FHR of SZ (FHR-SZ) or FHR of BP (FHR-BP) and PBC children as part of a register-based, prospective cohort-study; The Danish High Risk and Resilience study-VIA 11. We included 85 (44% female) FHR-SZ, 63 (52% female) FHR-BP and 98 (50% female) PBC in the analyses. Executive control effects, caused by the spatial visuomotor conflict, showed no differences between groups. Bayesian ANOVA of reaction time (RT) variability, quantified by the coefficient of variation (CVRT), revealed a group effect with similarly higher CVRT in FHR-BP and FHR-SZ compared to PBC (BF10 = 6.82). The fMRI analyses revealed no evidence for between-group differences in task-related brain activation. Post hoc analyses excluding children with psychiatric illness yielded same results. FHR-SZ and FHR-BP at age 11-12 show intact ability to resolve a spatial visuomotor conflict and neural efficacy. The increased variability in RT may reflect difficulties in maintaining sustained attention. Since variability in RT was independent of existing psychiatric illness, it may reflect a potential endophenotypic marker of risk.

Pre-trial and pre-response EEG microstates in schizophrenia: An endophenotypic marker

Cognitive deficits in Schizophrenia interfere with everyday functioning and social functioning. Strong familial associations in schizophrenia might serve to establish cognitive impairments as endophenotypic markers. Therefore, visuo-spatial working memory simulating day-to-day activities at high memory load was assessed in patients with schizophrenia, their first-degree relatives and healthy controls to explore pre-trial and pre-response EEG microstates and their intracranial generators. Twenty-eight patients with schizophrenia, first-degree relatives and matched healthy controls participated in the study. Brain activity during visuo-spatial working memory task was recorded using 128-channel electroencephalography. Pre-trial and pre-response microstate maps of correct and error trials were clustered across groups according to their topography. Microstate map parameters and underlying cortical sources were compared among groups. Pre-trial (correct) microstate Map 1 was significantly different between controls and patients which could qualify it as a state marker with its intracranial generator localized to right inferior frontal gyrus (rIFG). Pre-response (correct) microstate map was significantly different between controls and first-degree relatives which could be considered an endophenotypic marker for schizophrenia. No significant differences were observed for error trials between groups. rIFG which is involved in the execution of multi-component behaviour and selective inhibitory control could distinguish patients with schizophrenia from their first-degree relatives and healthy controls. Further, microstate based biomarkers have the potential to facilitate diagnosis of schizophrenia at a preclinical stage resulting in efficient diagnosis and better prognosis.

O4.2. HERITABILITY AND CORRELATION TO SCHIZOPHRENIA SPECTRUM DISORDER OF GLUTAMATE AND OTHER NEUROMETABOLITE LEVELS IN ANTERIOR CINGULATE AND LEFT THALAMUS: A REGISTER BASED MAGNETIC RESONANCE TWIN STUDY

BackgroundGlutamatergic changes in schizophrenia may precede dopaminergic alterations leading to psychopathology as part of a dopaminergic pathway, or they may represent a distinct pathophysiology. It is unknown if these glutamatergic alterations are due to genetic influences, although findings in gene studies implicate the NMDA receptor. Higher levels of glutamate and glutamine have been reported in the thalamus of patients with schizophrenia, while studies of the anterior cingulate cortex (ACC) have reported increased, decreased, and unaltered levels compared to healthy controls.By studying discordant mono- (MZ) and dizygotic (DZ) twins it is possible to estimate heritability and correlation to disease in the same population. This kind of study has only been done once on glutamate levels, but no heritability estimates were reported.1 A study of older healthy twins found N-acetyl aspartate (NAA), choline (Cho), creatinine (Cr), and myo-inositol (MI) levels to be heritable in posterior cingulate cortex.2 Of these metabolites, NAA has generally been found to correlate negatively with schizophrenia. Here we present our final results on heritability, and correlation to liability for schizophrenia spectrum disorder (ICD-10 F2x.x) of the neurometabolite levels in the ACC and the left thalamus.MethodsBy linking The Danish Twin Register and The Danish Psychiatric Central Research Register, 25 complete MZ and 21 complete DZ twin pairs con- or discordant for schizophrenia spectrum disorder (ICD 10 F2x.x) and 29 complete MZ and 20 complete DZ healthy control pairs were included. Thirteen additional twins were scanned without their siblings. Spectra of glutamate, Glx, NAA, Cho, Cr and MI were obtained by [1H]-MR spectroscopy at 3 tesla and analyzed by using LCModel. Additive genetic, common environmental and unique environmental effects on metabolite levels were calculated by structural equation modeling with openMX software. The best fitting model was determined by the Akaike Information Criterion.ResultsIn the ACC heritability estimates were significant for glutamate (29%), Glx (31%), NAA (39%), Cho (38%), Cr (37%) and MI (33%). In the left thalamus we found significant estimates of heritability for glutamate (16%), Glx (31%), Cho (60%), and of common environment for Cr (29%). A significant positive correlation to schizophrenia spectrum liability was found for glutamate in the left thalamus (r=0.16; p = 0.03), and negative correlations were found for NAA (r = -0.16; p = 0.02) and Cr (r = -0.25; p = 0.006) in the ACC. For glutamate in the thalamus and Cr in the ACC the significant correlation to disease was due to overlapping genetic effects influencing both metabolite and disease.DiscussionIn this the first study to estimate heritability of glutamate levels in the brain, the primary findings are that glutamate levels in both the ACC and the left thalamus are heritable, and in the left thalamus also correlated to disease with a significant genetic overlap. This emphasizes glutamate levels in the left thalamus as a potential endophenotypic marker for schizophrenia. NAA and Cr were negatively correlated to disease in the ACC, which could point to disturbances of neuronal health and metabolism. For Cr an overlap of genes influencing both metabolite levels and disease suggests Cr as a possible candidate endophenotype.

The N1 auditory evoked potential component as an endophenotype for schizophrenia: high-density electrical mapping in clinically unaffected first-degree relatives, first-episode, and chronic schizophrenia patients

The N1 component of the auditory evoked potential (AEP) is a robust and easily recorded metric of auditory sensory-perceptual processing. In patients with schizophrenia, a diminution in the amplitude of this component is a near-ubiquitous finding. A pair of recent studies has also shown this N1 deficit in first-degree relatives of schizophrenia probands, suggesting that the deficit may be linked to the underlying genetic risk of the disease rather than to the disease state itself. However, in both these studies, a significant proportion of the relatives had other psychiatric conditions. As such, although the N1 deficit represents an intriguing candidate endophenotype for schizophrenia, it remains to be shown whether it is present in a group of clinically unaffected first-degree relatives. In addition to testing first-degree relatives, we also sought to replicate the N1 deficit in a group of first-episode patients and in a group of chronic schizophrenia probands. Subject groups consisted of 35 patients with schizophrenia, 30 unaffected first-degree relatives, 13 first-episode patients, and 22 healthy controls. Subjects sat in a dimly lit room and listened to a series of simple 1,000-Hz tones, indicating with a button press whenever they heard a deviant tone (1,500 Hz; 17% probability), while the AEP was recorded from 72 scalp electrodes. Both chronic and first-episode patients showed clear N1 amplitude decrements relative to healthy control subjects. Crucially, unaffected first-degree relatives also showed a clear N1 deficit. This study provides further support for the proposal that the auditory N1 deficit in schizophrenia is linked to the underlying genetic risk of developing this disorder. In light of recent studies, these results point to the N1 deficit as an endophenotypic marker for schizophrenia. The potential future utility of this metric as one element of a multivariate endophenotype is discussed.

P.1.b.008 Post imperative negative variation as an endophenotypic marker of schizophrenia?

P.1.b.008 Post imperative negative variation as an endophenotypic marker of schizophrenia?

Lack of support for the inability to taste phenylthiocarbamide as an endophenotypic marker in patients with schizophrenia and their first-degree relatives

Objective This study sought to replicate recent findings that both patients and relatives are significantly more likely to be phenylthiocarbamide (PTC) nontasters than healthy controls, and that within the patient group, nontasters have more severe positive and/or negative symptoms than tasters. Associations between PTC-tasting status and olfactory identification scores also were examined. Method PTC perception and olfactory identification were assessed in 48 patients with schizophrenia or schizoaffective disorder, 28 first-degree relatives, and 32 healthy volunteers. Results The three groups did not differ in PTC taste sensitivity. Findings did not change after: a sensitivity analysis that re-categorized participants who “possibly” tasted PTC, excluding Caucasian participants, or restricting the sample of patients to only those with schizophrenia. Among the patients, tasters and nontasters did not differ with regard to positive, negative, or general psychopathology symptoms. In the combined sample and the three groups separately, there were no associations between PTC-tasting status and olfactory identification scores. Conclusions This study, conducted specifically as an attempt to replicate previously reported findings, failed to provide support for PTC perception as an endophenotypic marker for schizophrenia. Further research is warranted.

Therapeutic possibilities of cysteamine in the treatment of schizophrenia

Schizophrenia has complicated pathogeneses that is not able to be explained by any one supposed hypothesis, although alterations in dopamine neurotransmission have been widely accepted as the most plausible mechanism. A transition from traditional typical antipsychotics to contemporary atypical antipsychotics which have significantly improved tolerability and enhanced specific efficacy has been also made based on this dopamine hypothesis. Cysteamine is a natural product of mammalian cells and found to be useful pharmacological alternative. A number of evidence suggests that cysteamine may control directly or indirectly dopamine neurotransmission in nucleus accumbens and other schizophrenia-related brain regions. Systemic cysteamine injection mitigated the apomorphine-induced stereotypy as well as decreasing motor stimulant effects of amphetamine, which favor cysteamine over animal models of schizophrenia relative to hyperactivity of dopaminergic pathway. In addition, cysteamine showed neuroprotective effects by way of enhancing central and serum brain derived neurotrophic factor (BDNF) that has been proved to be altered in patients with schizophrenia. Antipsychotic drugs exert their effect partly by modifying the synthesis and distribution of BDNF in selected brain region. Cysteamine was effective to reverse a disruption in prepulse inhibition, an endophenotypic marker of schizophrenia. Cysteamine can also stimulate the release of cortical dopamine, which is interesting in that decreased dopaminergic function in the cerebral cortex has been repeatedly demonstrated in patients with schizophrenia and associated with prominent depressive and negative symptoms. Cysteamine can also increase an important antioxidant, glutathione. Finally, cysteamine treatment was found to decrease weight gain, cataleptic behavior, and serum prolactin levels, which are the major beneficial properties of contemporary atypical antipsychotics. Hence, further explorations of therapeutic implication of cysteamine for schizophrenia in preclinical studies should be warranted in future.

Early Visual Sensory Deficits as Endophenotypes for Schizophrenia

The imperative to establish so-called endophenotypes-quantifiable measures of risk for neurological dysfunction-is a growing focus of research in schizophrenia. Electrophysiological markers of sensory processing, observable in human event-related potentials, hold great promise in this regard, lying closer to underlying physiology than descriptive clinical diagnostic tests. Early visual processing deficits, as measured by clear amplitude reductions in the occipital P1 component of the visual event-related potential, have been repeatedly demonstrated in patients with schizophrenia. However, before P1 amplitude may be considered as an endophenotypic marker for schizophrenia, it is necessary to establish its sensitivity to genetic liability. Event-related potential responses to simple visual isolated-check stimuli were examined in 25 clinically unaffected first-degree relatives of patients with schizophrenia and 15 DSM-IV-diagnosed schizophrenia probands and compared with responses from 26 healthy, age-matched control subjects. Using high-density electrical scalp recordings, between-groups analysis assessed the integrity of the visual P1 component across the 3 groups. The study was conducted at St Vincent's Psychiatric Hospital in Fairview, Dublin, Ireland. Substantially reduced P1 amplitude was demonstrated in both relatives and probands compared with controls with topographical mapping and inverse source analysis localizing this deficit largely to midline regions in early visual sensory cortices and regions of the dorsal visual stream. Additional later differences between these groups, where the relatives actually show larger amplitude responses, may point toward compensatory mechanisms at play in relatives. Our findings demonstrate a deficit in early visual processing in clinically unaffected first-degree relatives of patients with schizophrenia, providing evidence that this deficit may serve as a genetic marker for this disorder. The efficacy of using P1 amplitude as an endophenotype is underscored by the observation of a large effect size (d=0.9) over scalp sites where the deficit was maximal.

Reaction time of the Continuous Performance Test is an endophenotypic marker for schizophrenia: A study of first-episode neuroleptic-naive schizophrenia, their non-psychotic first-degree relatives and healthy population controls

Sustained attention has been proposed as an endophenotype of schizophrenia, and consequently may be useful as a quantitative trait in genetic studies. In the present study, we used the continuous performance test (CPT) to measure sustained attention in 112 first-episode and neuroleptic-naive schizophrenic patients, 296 of their non-psychotic first-degree relatives, and 452 normal controls. Compared with controls, probands with schizophrenia showed worse performance on all measures of CPT. Parents, siblings and offspring of probands were also impaired on ‘hit reaction time′, an index of psychomotor processing speed of the correct response. Hit reaction time was also independent of the acute clinical features of the disease, indicating it is a trait rather than a state marker. Our findings supported the use of the hit reaction time measure of the CPT as an endophenotype marker for schizophrenia.

Relationship between Class I and II HLA Antigens in Schizophrenia and Eye Movement Disturbances: A Preliminary Study

The region coding human leukocyte antigen (HLA) on chromosome 6q21 was shown to be associated with both the vulnerability to schizophrenia and presence of eye movement disturbances (EMD). The aim of this preliminary study was to investigate how individual class I and II HLA antigens in schizophrenic patients may be related to schizophrenia and to the intensity of two kinds of EMD: fixation and smooth pursuit. The incidence of HLA antigens was compared between 40 schizophrenic patients (17 male, 23 female) and 198 healthy control subjects (112 male, 86 female). In schizophrenic patients, the intensity of EMD assessed by infrared reflectometry and quantified on a scale from 0 to 3 was correlated with the incidence of HLA antigens. A number of differences regarding HLA antigens were found between schizophrenic patients and healthy subjects. Significant correlation was also obtained between some EMD and a number of HLA antigens. Antigens A24 and A28 were found to occur in different frequencies in schizophrenic patients and healthy control subjects. They also correlated with EMD on the fixation and smooth pursuit tests. The results obtained show an association between HLA antigens and EMD as an endophenotypic marker of schizophrenia, and may add to other findings on susceptibility loci for schizophrenia on chromosome 6p21. A limitation of this study is a small number of investigated patients with schizophrenia.

Temporal stability of saccadic task performance in schizophrenia and bipolar patients

Identifying endophenotypes of schizophrenia will assist in the identification of individuals who are at heightened risk for the disorder. Investigators have proposed antisaccade task deficits as an endophenotypic marker of schizophrenia. However, the diagnostic specificity and the temporal stability of the task deficit are unresolved issues. To date, there are few published reports of test-retest stability of antisaccade task performance in psychiatric patients. Twenty-three schizophrenia out-patients and 10 bipolar out-patients were administered two saccadic (antisaccade and refixation) tasks at two separate assessments, with an average test retest interval of 33 months. The schizophrenia patients displayed high test-retest reliabilities of antisaccade task accuracy, despite changes in medication and clinical status. Additionally, the schizophrenia group's saccadic reaction times for antisaccade correct responses and task errors were moderately stable over time. In contrast, the bipolar patients did not show temporal stability in their antisaccade task accuracy or in their response latencies to either correct or incorrect antisaccade responses. The results are supportive of the trait-like characteristics of antisaccade task deficits in schizophrenia patients. These findings also suggest that antisaccade task deficits may serve as an endophenotypic marker of schizophrenia.

Smooth pursuit and antisaccade performance evidence trait stability in schizophrenia patients and their relatives

Several forms of eye movement dysfunction (EMD) have been widely regarded as candidate endophenotypes of schizophrenia, ultimately capable of identifying individuals carrying schizophrenia susceptibility genes and elucidating the pathophysiology of schizophrenia. As an indication of their trait-like status, candidate endophenotypes optimally evidence stability over time. However, there have been few published reports of test–retest reliability of several forms of EMD in schizophrenia patients and their relatives. In the current investigation, schizophrenia patients and the first-degree biological relatives of schizophrenia patients ( n=15) were administered by an eye movement battery including smooth pursuit, antisaccade and prosaccade tasks, and re-tested after an average of 1.82 years (range=14–24 months). Adequate test–retest reliabilities of smooth pursuit closed-loop gain (Pearson r=0.72), antisaccade error rate ( r=0.73), saccade reaction time to correct antisaccade responses ( r=0.73), and prosaccade hypometria ( r=0.72) were observed. Lower reliabilities were obtained for smooth pursuit open-loop gain ( r=0.52) and prosaccade reaction time ( r=0.43). The results are supportive of the trait-like characteristics of particular forms of EMD in schizophrenia families and of the candidacy of EMD as an endophenotypic marker of schizophrenia.