Intact Mismatch Negativity Responses in Clinical High Risk for Psychosis and First-Episode Psychosis: Evidence From Source-Reconstructed Event-Related Fields and Time-Frequency Data.

BACKGROUND: This study examined whether mismatch negativity (MMN) responses are impaired in participants at clinical high risk for psychosis (CHR-P) and patients with first-episode psychosis (FEP) and whether MMN deficits predict clinical outcomes in CHR-Ps. METHODS: Magnetoencephalography data were collected during a duration-deviant MMN paradigm for a group of 116 CHR-P participants, 33 FEP patients (15 antipsychotic-naïve), clinical high risk negative group (n = 38) with substance abuse and affective disorder, and 49 healthy control participants. Analysis of group differences of source-reconstructed event-related fields as well as time-frequency and intertrial phase coherence focused on the bilateral Heschl's gyri and bilateral superior temporal gyri. RESULTS: Significant magnetic MMN responses were found across participants in the bilateral Heschl's gyri and bilateral superior temporal gyri. However, MMN amplitude as well as time-frequency and intertrial phase coherence responses were intact in CHR-P participants and FEP patients compared with healthy control participants. Furthermore, MMN deficits were not related to persistent attenuated psychotic symptoms or transitions to psychosis in CHR-P participants. CONCLUSIONS: Our data suggest that magnetic MMN responses in magnetoencephalography data are not impaired in early-stage psychosis and may not predict clinical outcomes in CHR-P participants.

Thalamo-cortical circuits during sensory attenuation in emerging psychosis: a combined magnetoencephalography and dynamic causal modelling study.

Evidence suggests that schizophrenia (ScZ) involves impairments in sensory attenuation. It is currently unclear, however, whether such deficits are present during early-stage psychosis as well as the underlying network and the potential as a biomarker. To address these questions, Magnetoencephalography (MEG) was used in combination with computational modeling to examine M100 responses that involved a "passive" condition during which tones were binaurally presented, while in an "active" condition participants were asked to generate a tone via a button press. MEG data were obtained from 109 clinical high-risk for psychosis (CHR-P) participants, 23 people with a first-episode psychosis (FEP), and 48 healthy controls (HC). M100 responses at sensor and source level in the left and right thalamus (THA), Heschl's gyrus (HES), superior temporal gyrus (STG) and right inferior parietal cortex (IPL) were examined and dynamic causal modeling (DCM) was performed. Furthermore, the relationship between sensory attenuation and persistence of attenuated psychotic symptoms (APS) and transition to psychosis was investigated in CHR-P participants. Sensory attenuation was impaired in left HES, left STG and left THA in FEP patients, while in the CHR-P group deficits were observed only in right HES. DCM results revealed that CHR-P participants showed reduced top-down modulation from the right IPL to the right HES. Importantly, deficits in sensory attenuation did not predict clinical outcomes in the CHR-P group. Our results show that early-stage psychosis involves impaired sensory attenuation in auditory and thalamic regions but may not predict clinical outcomes in CHR-P participants.

Experiences of Stigma and Discrimination in Borderline Personality Disorder: A Systematic Review and Qualitative Meta-Synthesis.

Individuals with a diagnosis of borderline personality disorder (BPD) typically experience discrimination and stigma, resulting in poor identification and delayed care. We conducted a review to examine and synthesize qualitative studies exploring experiences of stigma and discrimination among individuals with BPD. In August 2021, we systematically searched the following databases: Embase, Medline, Cochrane Library, PsycINFO, and Cinhal. We also hand searched reference lists and Google Scholar. We then synthesized studies using meta-ethnography. We included seven articles in the study, all of high or moderate quality. Five themes were identified: (1) resistance from clinicians (withholding information), (2) othering, (3) negative impact on self-image/esteem, (4) hopelessness surrounding the perceived permanency of BPD, and (5) feeling like a burden. This review highlights the need for improved understanding of BPD across health care services. We also discussed the need to introduce a standardized pathway of care across health services following a BPD diagnosis.

Investigating temporal and prosodic markers in clinical high-risk for psychosis participants using automated acoustic analysis.

AIM: Language disturbances are a candidate biomarker for the early detection of psychosis. Temporal and prosodic abnormalities have been observed in schizophrenia patients, while there is conflicting evidence whether such deficits are present in participants meeting clinical high-risk for psychosis (CHR-P) criteria. METHODS: Clinical interviews from CHR-P participants (n = 50) were examined for temporal and prosodic metrics and compared against a group of healthy controls (n = 17) and participants with affective disorders and substance abuse (n = 23). RESULTS: There were no deficits in acoustic variables in the CHR-P group, while participants with affective disorders/substance abuse were characterized by slower speech rate, longer pauses and higher unvoiced frames percentage. CONCLUSION: Our finding suggests that temporal and prosodic aspects of speech are not impaired in early-stage psychosis. Further studies are required to clarify whether such abnormalities are present in sub-groups of CHR-P participants with elevated psychosis-risk.

Recruiting and exploring vulnerabilities among young people at risk, or in the early stages of serious mental illness (borderline personality disorder and first episode psychosis).

Introduction: Many gaps exist in our understanding of the developmental pathways to severe mental illness (SMI), including borderline personality disorder (BPD) and psychosis. However, those who have experienced adverse childhood experiences (ACEs) are at an increased risk and there is evidence to suggest that one of the earliest markers is emotional dysregulation. An area which has received relatively less research attention is the role neurodevelopmental disorders (NDDs) play. The aim of this feasibility study was therefore to explore the clinical profiles of young people early in the course of SMI, including their profiles of ACEs, emotional regulation difficulties, borderline personality traits and NDDs. Methods: A cross-sectional study of young people (aged 15-25) at risk of SMI, currently being seen within NHS mental health services, was conducted. This included those with early symptoms of psychosis and/or BPD as assessed by diagnostic interview. Eligible participants self-completed a battery of sociodemographic, clinical, and psychological measures in the company of a researcher. This included assessments of: symptoms of NDDs; borderline pathology traits; ACEs; and difficulties in emotional regulation. Statistical analyses included Mann-Whitney U tests and multiple regression. Results: Of the 118 potentially eligible participants who were referred, 48 were ultimately included in the study. Young people early in the course of SMI reported a high prevalence of ACEs and deficits in emotional regulation. In total, 79% met criteria for attention deficit hyperactivity disorder (ADHD) and/or autism spectrum disorder (ASD). Emotional dysregulation was found to significantly mediate the association between both ACEs and the frequency of NDDs and borderline personality traits, however given the small sample size these results are preliminary in nature. Conclusion: Young people early in the course of SMI are at an increased risk of experiencing multiple childhood adversities and our results indicate a high prevalence of NDDs amongst them. Emotional dysregulation emerged as a potentially significant early marker of future clinical severity. We suggest that the clinical implications of our findings include routine screening for NDDs and ACEs and an increased recognition of the significance of emotional dysregulation. However, larger scale longitudinal studies are needed to investigate these preliminary findings further.

Hippocampal structural alterations in early-stage psychosis: Specificity and relationship to clinical outcomes.

Hippocampal dysfunctions are a core feature of schizophrenia, but conflicting evidence exists whether volumetric and morphological changes are present in early-stage psychosis and to what extent these deficits are related to clinical trajectories. In this study, we recruited individuals at clinical high risk for psychosis (CHR-P) (n = 108), patients with a first episode of psychosis (FEP) (n = 37), healthy controls (HC) (n = 70) as well as a psychiatric control group with substance abuse and affective disorders (CHR-N: n = 38). MRI-data at baseline were obtained and volumetric as well as vertex analyses of the hippocampus were carried out. Moreover, volumetric changes were examined in the amygdala, caudate, nucleus accumbens, pallidum, putamen and thalamus. In addition, we obtained follow-up functional and symptomatic assessments in CHR-P individuals to examine the question whether anatomical deficits at baseline predicted clinical trajectories. Our results show that the hippocampus is the only structure showing significant volumetric decrease in early-stage psychosis, with FEPs showing significantly smaller hippocampal volumes bilaterally alongside widespread shape changes in the vertex analysis. For the CHR-P group, volumetric decreases were confined to the left hippocampus. However, hippocampal alterations in the CHR-P group were not robustly associated with clinical outcomes, including the persistence of attenuated psychotic symptoms and functional trajectories. Accordingly, our findings highlight that dysfunctions in hippocampal anatomy are an important feature of early-stage psychosis which may, however, not be related to clinical outcomes in CHR-P participants.

Gender, Addiction, and Removal of Children Into Care.

Introduction: Parental addiction can result in harm to children and removal of children by the Local Authority. Less is known about the impact of removal of children on their parents and whether gender has a role in this process. Methods: Data on 736 service users were obtained from the caseloads of 8 nurses and 12 social care workers from an Alcohol and Drug Recovery Service in Scotland. Gender differences in prevalence/patterns of child removal, associations between child removal and parental factors and the relationship between removal and suicidality were examined. Results: Mothers were more likely to have had one or more children removed compared to fathers (56.6 vs. 17.7%; p < 0.001) and were more likely to have a series of individual child removals (22.5 vs. 4.3%; p = 0.014). In addition to female gender, younger age, drug use, mental health and suicide attempts were also associated with child removal. Mothers who had children removed and women who were not mothers were more likely to have made an attempt to end their lives than women who had children but had not had them removed. Conclusion: Gender differences were apparent in prevalence and patterns of child removal. Mothers were six times more likely to have children removed compared to fathers. Child removal occurred alongside other risk factors suggesting that families need holistic support for their multiple areas of need. Services should be aware of the link between child removal and suicide and provide additional support to mothers during and after removal.

MR-Spectroscopy of GABA and Glutamate/Glutamine Concentrations in Auditory Cortex in Clinical High-Risk for Psychosis Individuals.

Psychosis involves changes in GABAergic and glutamatergic neurotransmission in auditory cortex that could be important for understanding sensory deficits and symptoms of psychosis. However, it is currently unclear whether such deficits are present in participants at clinical high-risk for psychosis (CHR-P) and whether they are associated with clinical outcomes. Magnetic Resonance Spectroscopy (MEGAPRESS, 1H-MRS at 3 Tesla) was used to estimate GABA, glutamate, and glutamate-plus-glutamine (Glx) levels in auditory cortex in a large sample of CHR-P (n = 99), CHR-N (clinical high-risk negative, n = 32), and 45 healthy controls. Examined were group differences in metabolite concentrations as well as relationships with clinical symptoms, general cognition, and 1-year follow-up clinical and general functioning in the CHR-P group. Results showed a marginal (p = 0.039) main group effect only for Glx, but not for GABA and glutamate concentrations, and only in left, not right, auditory cortex. This effect did not survive multiple comparison correction, however. Exploratory post-hoc tests revealed that there were significantly lower Glx levels (p = 0.029, uncorrected) in the CHR-P compared to the CHR-N group, but not relative to healthy controls (p = 0.058, uncorrected). Glx levels correlated with the severity of perceptual abnormalities and disorganized speech scores. However, in the CHR-P group, Glx levels did not predict clinical or functional outcomes. Accordingly, the findings from the present study suggest that MRS-measured GABA, glutamate and Glx levels in auditory cortex of CHR-P individuals are largely intact.

Characterising cognitive heterogeneity in individuals at clinical high-risk for psychosis: a cluster analysis with clinical and functional outcome prediction.

Schizophrenia is characterised by cognitive impairments that are already present during early stages, including in the clinical high-risk for psychosis (CHR-P) state and first-episode psychosis (FEP). Moreover, data suggest the presence of distinct cognitive subtypes during early-stage psychosis, with evidence for spared vs. impaired cognitive profiles that may be differentially associated with symptomatic and functional outcomes. Using cluster analysis, we sought to determine whether cognitive subgroups were associated with clinical and functional outcomes in CHR-P individuals. Data were available for 146 CHR-P participants of whom 122 completed a 6- and/or 12-month follow-up; 15 FEP participants; 47 participants not fulfilling CHR-P criteria (CHR-Ns); and 53 healthy controls (HCs). We performed hierarchical cluster analysis on principal components derived from neurocognitive and social cognitive measures. Within the CHR-P group, clusters were compared on clinical and functional variables and examined for associations with global functioning, persistent attenuated psychotic symptoms and transition to psychosis. Two discrete cognitive subgroups emerged across all participants: 45.9% of CHR-P individuals were cognitively impaired compared to 93.3% of FEP, 29.8% of CHR-N and 30.2% of HC participants. Cognitively impaired CHR-P participants also had significantly poorer functioning at baseline and follow-up than their cognitively spared counterparts. Specifically, cluster membership predicted functional but not clinical outcome. Our findings support the existence of distinct cognitive subgroups in CHR-P individuals that are associated with functional outcomes, with implications for early intervention and the understanding of underlying developmental processes.

Duration of basic and attenuated-psychotic symptoms in individuals at clinical high risk for psychosis: pattern of symptom onset and effects of duration on functioning and cognition.

INTRODUCTION: Duration of risk symptoms (DUR) in people at clinical high risk for psychosis (CHR-P) has been related to poorer clinical outcomes, such as reduced functioning, but it is currently unclear how different symptoms emerge as well as their link with cognitive deficits. To address these questions, we examined the duration of basic symptoms (BS) and attenuated psychotic symptoms (APS) in a sample of CHR-P participants to test the hypothesis that BS precede the manifestation of APS. As a secondary objective, we investigated the relationship between DUR, functioning and neuropsychological deficits. METHODS: Data from 134 CHR-P participants were assessed with the Comprehensive Assessment of At-Risk Mental State and the Schizophrenia Proneness Interview, Adult Version. Global, role and social functioning and neurocognition were assessed and compared to a sample of healthy controls (n = 57). RESULTS: In CHR-P participants who reported both APS and BS, onset of BS and APS was not significantly related. When divided into short and long BS duration ( 8 years), CHR-P participants with a longer duration of BS showed evidence for an onset of BS preceding APS (n = 8, p = 0.003). However, in the short BS duration group, APS showed evidence of preceding BS (n = 56, p = 0.020). Finally, there were no significant effects of DUR on cognition or functioning measures. CONCLUSION: The present findings do not support the view that APS constitute a secondary phenomenon to BS. Moreover, our data could also not confirm that DUR has a significant effect on functioning and cognitive deficits. These findings are discussed in the context of current theories regarding emerging psychosis and the importance of DUR.

40-Hz Auditory Steady-State Responses Characterize Circuit Dysfunctions and Predict Clinical Outcomes in Clinical High-Risk for Psychosis Participants: A Magnetoencephalography Study.

BACKGROUND: This study aimed to examine whether 40-Hz auditory steady-state responses (ASSRs) are impaired in participants at clinical high-risk for psychosis (CHR-P) and predict clinical outcomes. METHODS: Magnetoencephalography data were collected during a 40-Hz ASSR paradigm for a group of 116 CHR-P participants, 33 patients with first-episode psychosis (15 antipsychotic-naïve), a psychosis risk-negative group (n = 38), and 49 healthy control subjects. Analysis of group differences of 40-Hz intertrial phase coherence and 40-Hz amplitude focused on right Heschl's gyrus, superior temporal gyrus, hippocampus, and thalamus after establishing significant activations during 40-Hz ASSR stimulation. Linear regression and linear discriminant analyses were used to predict clinical outcomes in CHR-P participants, including transition to psychosis and persistence of attenuated psychotic symptoms (APSs). RESULTS: CHR-P participants and patients with first-episode psychosis were impaired in 40-Hz amplitude in the right thalamus and hippocampus. In addition, patients with first-episode psychosis were impaired in 40-Hz amplitude in the right Heschl's gyrus, and CHR-P participants in 40-Hz intertrial phase coherence in the right Heschl's gyrus. The 40-Hz ASSR deficits were pronounced in CHR-P participants who later transitioned to psychosis (n = 13) or showed persistent APSs (n = 34). Importantly, both APS persistence and transition to psychosis were predicted by 40-Hz ASSR impairments, with ASSR activity in the right hippocampus, superior temporal gyrus, and middle temporal gyrus correctly classifying 69.2% individuals with nonpersistent APSs and 73.5% individuals with persistent APSs (area under the curve = 0.842), and right thalamus 40-Hz activity correctly classifying 76.9% transitioned and 53.6% nontransitioned CHR-P participants (area under the curve = 0.695). CONCLUSIONS: Our data indicate that deficits in gamma-band entrainment in the primary auditory cortex and subcortical areas constitute a potential biomarker for predicting clinical outcomes in CHR-P participants.

The relationship between cognitive deficits and impaired short-term functional outcome in clinical high-risk for psychosis participants: A machine learning and modelling approach.

Poor functional outcomes are common in individuals at clinical high-risk for psychosis (CHR-P), but the contribution of cognitive deficits remains unclear. We examined the potential utility of cognitive variables in predictive models of functioning at baseline and follow-up with machine learning methods. Additional models fitted on baseline functioning variables were used as a benchmark to evaluate model performance. Data were available for 1) 146 CHR-P individuals of whom 118 completed a 6- and/or 12-month follow-up, 2) 47 participants not fulfilling CHR criteria (CHR-Ns) but displaying affective and substance use disorders and 3) 55 healthy controls (HCs). Predictors of baseline global assessment of functioning (GAF) scores were selected by L1-regularised least angle regression and then used to train classifiers to predict functional outcome in CHR-P individuals. In CHR-P participants, cognitive deficits together with clinical and functioning variables explained 41% of the variance in baseline GAF scores while cognitive variables alone explained 12%. These variables allowed classification of functional outcome with an average balanced accuracy (BAC) of 63% in both mixed- and cross-site models. However, higher accuracies (68%-70%) were achieved using classifiers fitted only on baseline functioning variables. Our findings suggest that cognitive deficits, alongside clinical and functioning variables, displayed robust relationships with impaired functioning in CHR-P participants at baseline and follow-up. Moreover, these variables allow for prediction of functional outcome. However, models based on baseline functioning variables showed a similar performance, highlighting the need to develop more accurate algorithms for predicting functional outcome in CHR-P participants.

Nature and nurture? A review of the literature on childhood maltreatment and genetic factors in the pathogenesis of borderline personality disorder.

BACKGROUND: Borderline Personality Disorder (BPD) is a psychiatric disorder associated with significant morbidity and mortality. However, the neurobiological alterations underlying the condition remain poorly understood. As a result, existing treatments remain inadequate. One of the main risk factors for the development of BPD is a history of childhood maltreatment. However, it is considered neither causative nor specific to the condition. Current theory is therefore increasingly moving toward a 'Gene x Environment' (GxE) model of the condition. The purpose of the current work was to conduct a systematic literature review, which comprehensively identifies all published molecular level GxE studies that have explored the role of specific genetic loci, in influencing the risk of BPD following exposure to childhood abuse or neglect. METHODS: Four electronic databases were used to systematically search for molecular level GxE studies of any design, which focused on the development of BPD following exposure to childhood abuse or neglect, without language or date restrictions. Articles were screened independently by two reviewers and results were synthesized narratively. RESULTS: A total of 473 articles were screened of which sixteen were selected for inclusion in our review. Implicated genes were categorised according to their influence on; Neurotransmitter Systems, Neurodevelopment and Neuroendocrine Systems. CONCLUSIONS: The identified studies have produced several relevant and statistically significant results. Of particular note, is the repeated finding that genes involved in HPA axis regulation, may be altered by exposure to childhood maltreatment, influencing subsequent susceptibility to BPD. This is both biologically plausible and of potential clinical significance.

Prevalence and predictors of suicidality and non-suicidal self-harm among individuals at clinical high-risk for psychosis: Results from a community-recruited sample.

AIM: Suicidal thoughts and behaviours are prevalent in individuals with schizophrenia. However, research examining the prevalence and predictors of suicidality and self-harm in participants at clinical high-risk for psychosis (CHR-P) is limited and mostly focuses on help-seeking participants recruited through clinical pathways. The current study sought to assess the prevalence of suicidality and self-harm and identify predictors of current suicidal ideation in community-recruited CHR-P participants. METHODS: Data were available for 130 CHR-P participants, 15 participants with first-episode psychosis (FEP), 47 participants not fulfilling CHR-P criteria (CHR-Ns) and 53 healthy controls. Current and lifetime suicidality and self-harm were assessed using the Mini-International Neuropsychiatric Interview and the Comprehensive Assessment of At-Risk Mental States (CAARMS). Multivariable logistic regression analysis was used to determine predictors of current suicidal ideation in the CHR-P group. RESULTS: A considerable proportion of CHR-P participants disclosed current suicidal ideation (34.6%). Overall, FEP individuals were at greatest risk, with considerably high prevalence rates for current suicidal ideation (73.3%), lifetime self-harm behaviour (60.0%) and lifetime suicide attempt (60.0%). In the CHR-P sample, current suicidal ideation was predicted by lifetime suicide attempts, lower CAARMS severity, impaired social functioning and greater comorbidity. CONCLUSIONS: Our findings suggest that suicidality and self-harm are highly prevalent in community-recruited CHR-P and FEP individuals. Accordingly, these results highlight the importance of further research into the determinants of suicidality and self-harm during at-risk and early stages of psychosis, and the implementation of intervention strategies to reduce adverse outcomes in these populations.

Mania symptoms in a Swedish longitudinal population study: The roles of childhood trauma and neurodevelopmental disorders.

BACKGROUND: Adult psychiatric disorders are associated with both childhood traumatic experiences (CTEs) and neurodevelopmental disorders (NDDs). CTEs and NDDs frequently co-occur in childhood, but their combined risk effect on the emergence of juvenile mania symptoms has not yet been examined. METHODS: In a population-representative Swedish twin study, CTEs and NDDs were assessed in 3,348 nine-year old twins born between 1998 and 2001, and treated as dichotomous predictors (any CTEs, any NDDs). Follow-up data were gathered at age 15 through parental reports of mania symptoms, yielding a symptom count score. RESULTS: Both CTEs and NDDs at age 9 contributed uniquely to an increase in mania symptoms at age 15. Children with both risk factors had 1.6 times the rate of mania symptoms as children with CTEs-only (Incidence rate ratio [IRR] 1.63, 95% CI 1.37-1.93), and 1.3 times the rate of mania symptoms as children with NDDs-only (IRR 1.26, 95% CI 1.06-1.50). There was no evidence for an interactive effect of CTEs and NDDs. NDDs showed a trend towards having a larger effect on mania symptoms than CTEs (NDDs-only vs. CTEs-only: IRR 1.29, 95% CI 0.99-1.68). LIMITATIONS: Although it is a strength of the study that the data on exposures and outcome were collected prospectively, parental recall of CTEs was required and CTEs may be under-reported. CONCLUSIONS: NDDs are at least as important as CTEs in the development of mania symptoms, and their risk is additive. Those with a history of both CTEs and NDDs should be monitored closely for the development of more severe psychiatric presentations.