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The N100, an early auditory event-related potential, has been found to be altered in patients with psychosis. However, it is unclear if the N100 is a psychosis endophenotype that is also altered in the relatives of patients.
We conducted a family study using the auditory oddball paradigm to compare the N100 amplitude and latency across 243 patients with psychosis, 86 unaffected relatives, and 194 controls. We then conducted a systematic review and a random-effects meta-analysis pooling our results and 14 previously published family studies. We compared data from a total of 999 patients, 1192 relatives, and 1253 controls in order to investigate the evidence and degree of N100 differences.
In our family study, patients showed reduced N100 amplitudes and prolonged N100 latencies compared to controls, but no significant differences were found between unaffected relatives and controls. The meta-analysis revealed a significant reduction of the N100 amplitude and delay of the N100 latency in both patients with psychosis (standardized mean difference [s.m.d.] = −0.48 for N100 amplitude and s.m.d. = 0.43 for N100 latency) and their relatives (s.m.d. = − 0.19 for N100 amplitude and s.m.d. = 0.33 for N100 latency). However, only the N100 latency changes in relatives remained significant when excluding studies with affected relatives.
N100 changes, especially prolonged N100 latencies, are present in both patients with psychosis and their relatives, making the N100 a promising endophenotype for psychosis. Such changes in the N100 may reflect changes in early auditory processing underlying the etiology of psychosis.
Diminished sensory gating (SG) is a robust finding in psychotic disorders, but studies of early psychosis (EP) are rare. It is unknown whether SG deficit leads to poor neurocognitive, social, and/or real-world functioning. This study aimed to explore the longitudinal relationships between SG and these variables.
Seventy-nine EP patients and 88 healthy controls (HCs) were recruited at baseline. Thirty-three and 20 EP patients completed 12-month and 24-month follow-up, respectively. SG was measured using the auditory dual-click (S1 & S2) paradigm and quantified as P50 ratio (S2/S1) and difference (S1-S2). Cognition, real-life functioning, and symptoms were assessed using the MATRICS Consensus Cognitive Battery, Global Functioning: Social (GFS) and Role (GFR), Multnomah Community Ability Scale (MCAS), Awareness of Social Inference Test (TASIT), and the Positive and Negative Syndrome Scale (PANSS). Analysis of variance (ANOVA), chi-square, mixed model, correlation and regression analyses were used for group comparisons and relationships among variables controlling for potential confounding variables.
In EP patients, P50 ratio (p < 0.05) and difference (p < 0.001) at 24-month showed significant differences compared with that at baseline. At baseline, P50 indices (ratio, S1-S2 difference, S1) were independently associated with GFR in HCs (all p < 0.05); in EP patients, S2 amplitude was independently associated with GFS (p = 0.037). At 12-month and 24-month, P50 indices (ratio, S1, S2) was independently associated with MCAS (all p < 0.05). S1-S2 difference was a trending predictor of future function (GFS or MCAS).
SG showed progressive reduction in EP patients. P50 indices were related to real-life functioning.
Deficits in event-related potential (ERP) including duration mismatch negativity (MMN) and P3a have been demonstrated widely in chronic schizophrenia (SZ) but inconsistent findings were reported in first-episode patients. Psychotropic medications and diagnosis might contribute to different findings on MMN/P3a ERP in first-episode patients. The present study examined MMN and P3a in first episode drug naïve SZ and bipolar disorder (BPD) patients and explored the relationships among ERPs, neurocognition and global functioning.
Twenty SZ, 24 BPD and 49 age and sex-matched healthy controls were enrolled in this study. Data of clinical symptoms [Positive and Negative Symptoms Scale (PANSS), Young Manic Rating Scale (YMRS), Hamilton Depression Rating Scale (HAMD)], neurocognition [Wechsler Adult Intelligence Scale (WAIS), Cattell's Culture Fair Intelligence Test (CCFT), Delay Matching to Sample (DMS), Rapid Visual Information Processing (RVP)], and functioning [Functioning Assessment Short Test (FAST)] were collected. P3a and MMN were elicited using a passive auditory oddball paradigm.
Significant MMN and P3a deficits and impaired neurocognition were found in both SZ and BPD patients. In SZ, MMN was significantly correlated with FAST (r = 0.48) and CCFT (r = −0.31). In BPD, MMN was significantly correlated with DMS (r = −0.54). For P3a, RVP and FAST scores were significant predictors in SZ, whereas RVP, WAIS and FAST were significant predictors in BPD.
The present study found deficits in MMN, P3a, neurocognition in drug naïve SZ and BPD patients. These deficits appeared to link with levels of higher-order cognition and functioning.
Glucagon-like peptide-1 receptors (GLP-1Rs) are widely expressed in the brain. Evidence suggests that they may play a role in reward responses and neuroprotection. However, the association of GLP-1R with anhedonia and depression diagnosis has not been studied. Here, we examined the association of GLP-1R polymorphisms with objective and subjective measures of anhedonia, as well as depression diagnosis.
Objective [response bias assessed by the probabilistic reward task (PRT)] and subjective [Snaith-Hamilton Pleasure Scale (SHAPS)] measures of anhedonia, clinical variables and DNA samples were collected from 100 controls and 164 patients at McLean Hospital. An independent sample genotyped as part of the Psychiatric Genomics Consortium (PGC) was used to study the effect of putative GLP-1R polymorphisms linked to response bias in PRT on depression diagnosis.
The C allele in rs1042044 was significantly associated with increased PRT response bias, when controlling for age, sex, case-control status and PRT discriminability. AA genotype of rs1042044 showed higher anhedonia phenotype based on SHAPS scores. However, analysis of PGC major depressive disorder data showed no association between rs1042044 and depression diagnosis.
Findings suggest a possible association of rs1042044 with anhedonia but no association with depression diagnosis.
There is increasing evidence for shared genetic susceptibility between schizophrenia and bipolar disorder. Although genetic variants only convey subtle increases in risk individually, their combination into a polygenic risk score constitutes a strong disease predictor.
To investigate whether schizophrenia and bipolar disorder polygenic risk scores can distinguish people with broadly defined psychosis and their unaffected relatives from controls.
Using the latest Psychiatric Genomics Consortium data, we calculated schizophrenia and bipolar disorder polygenic risk scores for 1168 people with psychosis, 552 unaffected relatives and 1472 controls.
Patients with broadly defined psychosis had dramatic increases in schizophrenia and bipolar polygenic risk scores, as did their relatives, albeit to a lesser degree. However, the accuracy of predictive models was modest.
Although polygenic risk scores are not ready for clinical use, it is hoped that as they are refined they could help towards risk reduction advice and early interventions for psychosis.
Declaration of interest
R.M.M. has received honoraria for lectures from Janssen, Lundbeck, Lilly, Otsuka and Sunovian.
Twin studies have lacked statistical power to apply advanced genetic modelling techniques to the search for cognitive endophenotypes for bipolar disorder.
To quantify the shared genetic variability between bipolar disorder and cognitive measures.
Structural equation modelling was performed on cognitive data collected from 331 twins/siblings of varying genetic relatedness, disease status and concordance for bipolar disorder.
Using a parsimonious AE model, verbal episodic and spatial working memory showed statistically significant genetic correlations with bipolar disorder (rg = |0.23|–|0.27|), which lost statistical significance after covarying for affective symptoms. Using an ACE model, IQ and visual-spatial learning showed statistically significant genetic correlations with bipolar disorder (rg = |0.51|–|1.00|), which remained significant after covarying for affective symptoms.
Verbal episodic and spatial working memory capture a modest fraction of the bipolar diathesis. IQ and visual-spatial learning may tap into genetic substrates of non-affective symptomatology in bipolar disorder.
Subtle abnormalities in frontal white matter have been reported in
To assess whether impaired integrity of white matter tracts is associated
with bipolar disorder and genetic liability for the disorder.
A total of 19 patients with psychotic bipolar I disorder from multiply
affected families, 21 unaffected first-degree relatives and 18 comparison
individuals (controls) underwent diffusion tensor imaging. Whole brain
voxel-based analyses compared fractional anisotropy between patients and
relatives with controls, and its relationship with a quantitative measure
of genetic liability.
Patients had decreased fractional anisotropy compared with controls in
the genu of the corpus callosum, right inferior longitudinal fasciculus
and left superior longitudinal fasciculus. Increased genetic liability
for bipolar disorder was associated with reduced fractional anisotropy
across distributed regions of white matter in patients and their
Disturbed structural integrity within key intra- and interhemispheric
tracts characterises both bipolar disorder and genetic liability for this
We analysed Stroop (neuropsychological screening test) measures of response
inhibition in 18 twin pairs discordant for bipolar I disorder compared with
17 healthy control pairs, as well as 40 singletons with bipolar disorder
with psychotic features and a family history of psychosis, 46 of their
first-degree relatives without bipolar disorder or psychosis and 48
controls. In both studies, individuals with bipolar disorder showed Stroop
deficits and their first-degree relatives showed intact performance. In the
twin patients, an interference score was associated with depressive
symptoms. Having a first-degree relative with bipolar disorder, even a
familial, psychotic form, did not confer risk for enhanced susceptibility to
interference in our studies.
Background. Electrophysiological endophenotypes are far less explored in bipolar disorder as compared to schizophrenia. No previous twin study of event-related potentials (ERPs) in bipolar illness has been reported. This study uses a twin design and advanced genetic model fitting analyses aiming to (1) assess and quantify the relationship of a range of ERP components with bipolar disorder with psychotic features, and (2) examine the source of the relationship (due to genetic or environmental factors).
Method. P300, P50 suppression and mismatch negativity (MMN) were recorded in 10 discordant monozygotic (MZ) bipolar twin pairs, six concordant MZ bipolar twin pairs and 78 control twin pairs. Statistical analyses were based on structural equation modelling.
Results. Bipolar disorder was significantly associated with smaller P300 amplitude and decreased P50 suppression. Genetic correlations were the main source of the associations, estimated to be −0·33 for P300 amplitude and 0·46 for P50 ratio. Individual-specific environmental influences were not significant. MMN and P300 latency were not associated with the illness.
Conclusions. The results provide supporting evidence that P300 amplitude and P50 suppression ratio are ERP endophenotypes for bipolar disorder.
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