Meta-analytic prevalence of comorbid mental disorders in individuals at clinical high risk of psychosis: the case for transdiagnostic assessment.

Comorbid mental disorders in subjects at clinical high risk for psychosis (CHR-P) may impact preventive care. We conducted a PRISMA/MOOSE-compliant systematic meta-analysis, searching PubMed/PsycInfo up to June 21st, 2021 for observational studies/randomized controlled trials reporting on comorbid DSM/ICD-mental disorders in CHR-P subjects ( protocol ). The primary and secondary outcomes were baseline and follow-up prevalence of comorbid mental disorders. We also explored the association of comorbid mental disorders compared with CHR-P versus psychotic/non-psychotic control groups, their impact on baseline functioning and transition to psychosis. We conducted random-effects meta-analyses, meta-regression, and assessed heterogeneity/publication bias/quality (Newcastle Ottawa Scale, NOS). We included 312 studies (largest meta-analyzed sample = 7834, any anxiety disorder, mean age = 19.98 (3.40), females = 43.88%, overall NOS > 6 in 77.6% of studies). The prevalence was 0.78 (95% CI = 0.73-0.82, k = 29) for any comorbid non-psychotic mental disorder, 0.60 (95% CI = 0.36-0.84, k = 3) for anxiety/mood disorders, 0.44 (95% CI = 0.39-0.49, k = 48) for any mood disorders, 0.38 (95% CI = 0.33-0.42, k = 50) for any depressive disorder/episode, 0.34 (95% CI = 0.30-0.38, k = 69) for any anxiety disorder, 0.30 (95% CI 0.25-0.35, k = 35) for major depressive disorders, 0.29 (95% CI, 0.08-0.51, k = 3) for any trauma-related disorder, 0.23 (95% CI = 0.17-0.28, k = 24) for any personality disorder, and <0.23 in other mental disorders (I2 > 50% in 71.01% estimates). The prevalence of any comorbid mental disorder decreased over time (0.51, 95% CI = 0.25-0.77 over 96 months), except any substance use which increased (0.19, 95% CI = 0.00-0.39, k = 2, >96 months). Compared with controls, the CHR-P status was associated with a higher prevalence of anxiety, schizotypal personality, panic, and alcohol use disorders (OR from 2.90 to 1.54 versus without psychosis), a higher prevalence of anxiety/mood disorders (OR = 9.30 to 2.02) and lower prevalence of any substance use disorder (OR = 0.41, versus psychosis). Higher baseline prevalence of alcohol use disorder/schizotypal personality disorder was negatively associated with baseline functioning (beta from -0.40 to -0.15), while dysthymic disorder/generalized anxiety disorder with higher functioning (beta 0.59 to 1.49). Higher baseline prevalence of any mood disorder/generalized anxiety disorder/agoraphobia (beta from -2.39 to -0.27) was negatively associated with transition to psychosis. In conclusion, over three-quarters of CHR-P subjects have comorbid mental disorders, which modulate baseline functionig and transition to psychosis. Transdiagnostic mental health assessment should be warranted in subjects at CHR-P.

The Relationship Between Grey Matter Volume and Clinical and Functional Outcomes in People at Clinical High Risk for Psychosis.

Objective: To examine the association between baseline alterations in grey matter volume (GMV) and clinical and functional outcomes in people at clinical high risk (CHR) for psychosis. Methods: 265 CHR individuals and 92 healthy controls were recruited as part of a prospective multi-center study. After a baseline assessment using magnetic resonance imaging (MRI), participants were followed for at least two years to determine clinical and functional outcomes, including transition to psychosis (according to the Comprehensive Assessment of an At Risk Mental State, CAARMS), level of functioning (according to the Global Assessment of Functioning), and symptomatic remission (according to the CAARMS). GMV was measured in selected cortical and subcortical regions of interest (ROI) based on previous studies (ie orbitofrontal gyrus, cingulate gyrus, gyrus rectus, inferior temporal gyrus, parahippocampal gyrus, striatum, and hippocampus). Using voxel-based morphometry, we analysed the relationship between GMV and clinical and functional outcomes. Results: Within the CHR sample, a poor functional outcome (GAF < 65) was associated with relatively lower GMV in the right striatum at baseline (P < .047 after Family Wise Error correction). There were no significant associations between baseline GMV and either subsequent remission or transition to psychosis. Conclusions: In CHR individuals, lower striatal GMV was associated with a poor level of overall functioning at follow-up. This finding was not related to effects of antipsychotic or antidepressant medication. The failure to replicate previous associations between GMV and later psychosis onset, despite studying a relatively large sample, is consistent with the findings of recent large-scale multi-center studies.

Construct validity for computational linguistic metrics in individuals at clinical risk for psychosis: Associations with clinical ratings.

Language deficits are prevalent in psychotic illness, including its risk states, and are related to marked impairment in functioning. It is therefore important to characterize language impairment in the psychosis spectrum in order to develop potential preventive interventions. Natural language processing (NLP) metrics of semantic coherence and syntactic complexity have been used to discriminate schizophrenia patients from healthy controls (HC) and predict psychosis onset in individuals at clinical high-risk (CHR) for psychosis. To date, no studies have yet examined the construct validity of key NLP features with respect to clinical ratings of thought disorder in a CHR cohort. Herein we test the association of key NLP metrics of coherence and complexity with ratings of positive and negative thought disorder, respectively, in 60 CHR individuals, using Andreasen's Scale of Assessment of Thought, Language and Communication (TLC) Scale to measure of positive and negative thought disorder. As hypothesized, in CHR individuals, the NLP metric of semantic coherence was significantly correlated with positive thought disorder severity and the NLP metrics of complexity (sentence length and determiner use) were correlated with negative thought disorder severity. The finding of construct validity supports the premise that NLP analytics, at least in respect to core features of reduction of coherence and complexity, are capturing clinically relevant language disturbances in risk states for psychosis. Further psychometric study is required, in respect to reliability and other forms of validity.

Adverse clinical outcomes in people at clinical high-risk for psychosis related to altered interactions between hippocampal activity and glutamatergic function.

Preclinical rodent models suggest that psychosis involves alterations in the activity and glutamatergic function in the hippocampus, driving dopamine activity through projections to the striatum. The extent to which this model applies to the onset of psychosis in clinical subjects is unclear. We assessed whether interactions between hippocampal glutamatergic function and activity/striatal connectivity are associated with adverse clinical outcomes in people at clinical high-risk (CHR) for psychosis. We measured functional Magnetic Resonance Imaging of hippocampal activation/connectivity, and 1H-Magnetic Resonance Spectroscopy of hippocampal glutamatergic metabolites in 75 CHR participants and 31 healthy volunteers. At follow-up, 12 CHR participants had transitioned to psychosis and 63 had not. Within the clinical high-risk cohort, at follow-up, 35 and 17 participants had a poor or a good functional outcome, respectively. The onset of psychosis (ppeakFWE = 0.003, t = 4.4, z = 4.19) and a poor functional outcome (ppeakFWE < 0.001, t = 5.52, z = 4.81 and ppeakFWE < 0.001, t = 5.25, z = 4.62) were associated with a negative correlation between the hippocampal activation and hippocampal Glx concentration at baseline. In addition, there was a negative association between hippocampal Glx concentration and hippocampo-striatal connectivity (ppeakFWE = 0.016, t = 3.73, z = 3.39, ppeakFWE = 0.014, t = 3.78, z = 3.42, ppeakFWE = 0.011, t = 4.45, z = 3.91, ppeakFWE = 0.003, t = 4.92, z = 4.23) in the total CHR sample, not seen in healthy volunteers. As predicted by preclinical models, adverse clinical outcomes in people at risk for psychosis are associated with altered interactions between hippocampal activity and glutamatergic function.

Reciprocal Social Behavior and Related Social Outcomes in Individuals at Clinical High Risk for Psychosis.

Reciprocal social behavior (RSB) deficits have been noted in formal psychotic disorders and may play a role in the clinical high-risk for psychosis (CHR) syndrome. The present study examined RSB deficits and clinical and social functioning correlates in 45 individuals meeting criteria for a CHR syndrome and 47 healthy comparisons (HC). Further, this study examined associations with number of friends, problematic social Internet use, and perceived social support. Compared to the HC group, the CHR group exhibited greater deficits in total RSB and in all RSB subdomains. Total RSB deficits were associated with greater negative but not positive symptom severity in the CHR group, and greater social functional impairment. RSB deficits also may have related to fewer friendships, more problematic social Internet use, and less perceived belonging and tangible social support, although relationships with Internet use and perceived social support did not survive FDR-correction. These findings provide further evidence that RSB is impaired in the CHR syndrome and suggest specific social outcomes that may be affected. Further investigations with larger, diverse samples and repeated measures can confirm these findings.

Interactions between hippocampal activity and striatal dopamine in people at clinical high risk for psychosis: relationship to adverse outcomes.

Preclinical models propose that increased hippocampal activity drives subcortical dopaminergic dysfunction and leads to psychosis-like symptoms and behaviors. Here, we used multimodal neuroimaging to examine the relationship between hippocampal regional cerebral blood flow (rCBF) and striatal dopamine synthesis capacity in people at clinical high risk (CHR) for psychosis and investigated its association with subsequent clinical and functional outcomes. Ninety-five participants (67 CHR and 28 healthy controls) underwent arterial spin labeling MRI and 18F-DOPA PET imaging at baseline. CHR participants were followed up for a median of 15 months to determine functional outcomes with the global assessment of function (GAF) scale and clinical outcomes using the comprehensive assessment of at-risk mental states (CAARMS). CHR participants with poor functional outcomes (follow-up GAF < 65, n = 25) showed higher rCBF in the right hippocampus compared to CHRs with good functional outcomes (GAF ≥ 65, n = 25) (pfwe = 0.026). The relationship between rCBF in this right hippocampal region and striatal dopamine synthesis capacity was also significantly different between groups (pfwe = 0.035); the association was negative in CHR with poor outcomes (pfwe = 0.012), but non-significant in CHR with good outcomes. Furthermore, the correlation between right hippocampal rCBF and striatal dopamine function predicted a longitudinal increase in the severity of positive psychotic symptoms within the total CHR group (p = 0.041). There were no differences in rCBF, dopamine, or their associations in the total CHR group relative to controls. These findings indicate that altered interactions between the hippocampus and the subcortical dopamine system are implicated in the pathophysiology of adverse outcomes in the CHR state.

Integrated metastate functional connectivity networks predict change in symptom severity in clinical high risk for psychosis.

The ability to identify biomarkers of psychosis risk is essential in defining effective preventive measures to potentially circumvent the transition to psychosis. Using samples of people at clinical high risk for psychosis (CHR) and Healthy controls (HC) who were administered a task fMRI paradigm, we used a framework for labelling time windows of fMRI scans as 'integrated' FC networks to provide a granular representation of functional connectivity (FC). Periods of integration were defined using the 'cartographic profile' of time windows and k-means clustering, and sub-network discovery was carried out using Network Based Statistics (NBS). There were no network differences between CHR and HC groups. Within the CHR group, using integrated FC networks, we identified a sub-network negatively associated with longitudinal changes in the severity of psychotic symptoms. This sub-network comprised brain areas implicated in bottom-up sensory processing and in integration with motor control, suggesting it may be related to the demands of the fMRI task. These data suggest that extracting integrated FC networks may be useful in the investigation of biomarkers of psychosis risk.

Structure of positive psychotic symptoms in individuals at clinical high risk for psychosis.

AIM: Positive symptoms are a critical dimension of psychopathology in psychotic disorders and are used as a criterion for diagnosis across the psychosis continuum. Although initially considered as one dimension, there is evidence for multidimensionality within positive symptoms. The positive symptom structure has not been examined in individuals at clinical high risk (CHR) for psychosis. Knowledge of the dimensional structure of positive symptoms within CHR may contribute to our understanding of the aetiology and trajectory of this key facet of psychosis. METHOD: Exploratory factor analysis (EFA) was conducted on the Prodromal Questionnaire-Brief for 183 individuals meeting CHR criteria. Internal consistency was examined to determine the hierarchical structure of the data and alternative models were compared. RESULTS: EFA revealed a three factor model, grouping in to: perceptual abnormalities, grandiose/unusual delusions and persecutory/thought delusions, with a general factor accounting for 56% of the variance. Confirmatory factor analysis showed that a hierarchical model was the best fit. One item referring to nihilistic thoughts did not load on any factor. CONCLUSION: There is a clear three-dimensional model, distinguishing perceptual abnormalities, and two subgroups of delusions in CHR individuals. The factors are similar to those found in psychotic disorders. The identification and comparison of symptomatic models is useful given the prominent role positive symptoms play in diagnosis, and is crucial to our understanding of the clinical progression of psychosis. This work may provide a useful tool for future studies examining correlations with varying symptom factors and disease progression in CHR.

Neural Circuitry of Novelty Salience Processing in Psychosis Risk: Association With Clinical Outcome.

Psychosis has been proposed to develop from dysfunction in a hippocampal-striatal-midbrain circuit, leading to aberrant salience processing. Here, we used functional magnetic resonance imaging (fMRI) during novelty salience processing to investigate this model in people at clinical high risk (CHR) for psychosis according to their subsequent clinical outcomes. Seventy-six CHR participants as defined using the Comprehensive Assessment of At-Risk Mental States (CAARMS) and 31 healthy controls (HC) were studied while performing a novelty salience fMRI task that engaged an a priori hippocampal-striatal-midbrain circuit of interest. The CHR sample was then followed clinically for a mean of 59.7 months (~5 y), when clinical outcomes were assessed in terms of transition (CHR-T) or non-transition (CHR-NT) to psychosis (CAARMS criteria): during this period, 13 individuals (17%) developed a psychotic disorder (CHR-T) and 63 did not. Functional activation and effective connectivity within a hippocampal-striatal-midbrain circuit were compared between groups. In CHR individuals compared to HC, hippocampal response to novel stimuli was significantly attenuated (P = .041 family-wise error corrected). Dynamic Causal Modelling revealed that stimulus novelty modulated effective connectivity from the hippocampus to the striatum, and from the midbrain to the hippocampus, significantly more in CHR participants than in HC. Conversely, stimulus novelty modulated connectivity from the midbrain to the striatum significantly less in CHR participants than in HC, and less in CHR participants who subsequently developed psychosis than in CHR individuals who did not become psychotic. Our findings are consistent with preclinical evidence implicating hippocampal-striatal-midbrain circuit dysfunction in altered salience processing and the onset of psychosis.

Association of Adverse Outcomes With Emotion Processing and Its Neural Substrate in Individuals at Clinical High Risk for Psychosis.

Importance: The development of adverse clinical outcomes in patients with psychosis has been associated with behavioral and neuroanatomical deficits related to emotion processing. However, the association between alterations in brain regions subserving emotion processing and clinical outcomes remains unclear. Objective: To examine the association between alterations in emotion processing and regional gray matter volumes in individuals at clinical high risk (CHR) for psychosis, and the association with subsequent clinical outcomes. Design, Setting, and Participants: This naturalistic case-control study with clinical follow-up at 12 months was conducted from July 1, 2010, to August 31, 2016, and collected data from 9 psychosis early detection centers (Amsterdam, Basel, Cologne, Copenhagen, London, Melbourne, Paris, The Hague, and Vienna). Participants (213 individuals at CHR and 52 healthy controls) were enrolled in the European Network of National Schizophrenia Networks Studying Gene-Environment Interactions (EU-GEI) project. Data were analyzed from October 1, 2018, to April 24, 2019. Main Measures and Outcomes: Emotion recognition was assessed with the Degraded Facial Affect Recognition Task. Three-Tesla magnetic resonance imaging scans were acquired from all participants, and gray matter volume was measured in regions of interest (medial prefrontal cortex, amygdala, hippocampus, and insula). Clinical outcomes at 12 months were evaluated for transition to psychosis using the Comprehensive Assessment of At-Risk Mental States criteria, and the level of overall functioning was measured through the Global Assessment of Functioning [GAF] scale. Results: A total of 213 individuals at CHR (105 women [49.3%]; mean [SD] age, 22.9 [4.7] years) and 52 healthy controls (25 women [48.1%]; mean [SD] age, 23.3 [4.0] years) were included in the study at baseline. At the follow-up within 2 years of baseline, 44 individuals at CHR (20.7%) had developed psychosis and 169 (79.3%) had not. Of the individuals at CHR reinterviewed with the GAF, 39 (30.0%) showed good overall functioning (GAF score, ≥65), whereas 91 (70.0%) had poor overall functioning (GAF score, <65). Within the CHR sample, better anger recognition at baseline was associated with worse functional outcome (odds ratio [OR], 0.88; 95% CI, 0.78-0.99; P = .03). In individuals at CHR with a good functional outcome, positive associations were found between anger recognition and hippocampal volume (ze = 3.91; familywise error [FWE] P = .02) and between fear recognition and medial prefrontal cortex volume (z = 3.60; FWE P = .02), compared with participants with a poor outcome. The onset of psychosis was not associated with baseline emotion recognition performance (neutral OR, 0.93; 95% CI, 0.79-1.09; P = .37; happy OR, 1.03; 95% CI, 0.84-1.25; P = .81; fear OR, 0.98; 95% CI, 0.85-1.13; P = .77; anger OR, 1.00; 95% CI, 0.89-1.12; P = .96). No difference was observed in the association between performance and regional gray matter volumes in individuals at CHR who developed or did not develop psychosis (FWE P < .05). Conclusions and Relevance: In this study, poor functional outcome in individuals at CHR was found to be associated with baseline abnormalities in recognizing negative emotion. This finding has potential implications for the stratification of individuals at CHR and suggests that interventions that target socioemotional processing may improve functional outcomes.

Glutamatergic and dopaminergic function and the relationship to outcome in people at clinical high risk of psychosis: a multi-modal PET-magnetic resonance brain imaging study.

Preclinical models of psychosis propose that hippocampal glutamatergic neuron hyperactivity drives increased striatal dopaminergic activity, which underlies the development of psychotic symptoms. The aim of this study was to examine the relationship between hippocampal glutamate and subcortical dopaminergic function in people at clinical high risk for psychosis, and to assess the association with the development of psychotic symptoms. 1H-MRS was used to measure hippocampal glutamate concentrations, and 18F-DOPA PET was used to measure dopamine synthesis capacity in 70 subjects (51 people at clinical high risk for psychosis and 19 healthy controls). Clinical assessments were undertaken at baseline and follow-up (median 15 months). Striatal dopamine synthesis capacity predicted the worsening of psychotic symptoms at follow-up (r = 0.35; p < 0.05), but not transition to a psychotic disorder (p = 0.22), and was not significantly related to hippocampal glutamate concentration (p = 0.13). There were no differences in either glutamate (p = 0.5) or dopamine (p = 0.5) measures in the total patient group relative to controls. Striatal dopamine synthesis capacity at presentation predicts the subsequent worsening of sub-clinical total and psychotic symptoms, consistent with a role for dopamine in the development of psychotic symptoms, but is not strongly linked to hippocampal glutamate concentrations.

Association of Hippocampal Glutamate Levels With Adverse Outcomes in Individuals at Clinical High Risk for Psychosis.

Importance: Preclinical and human data suggest that hippocampal dysfunction plays a critical role in the onset of psychosis. Neural hyperactivity in the hippocampus is thought to drive an increase in subcortical dopamine function through glutamatergic projections to the striatum. Objective: To examine the association between hippocampal glutamate levels in individuals at clinical high risk for psychosis and their subsequent clinical outcomes. Design, Setting, and Participants: This cross-sectional study of 86 individuals at clinical high risk for psychosis and 30 healthy control individuals, with a mean follow-up of 18.5 months, was conducted between November 1, 2011, and November 1, 2017, at early detection services in London and Cambridge, United Kingdom. Main Outcomes and Measures: Concentrations of glutamate and other metabolites were measured in the left hippocampus using 3-T proton magnetic resonance spectroscopy at the first clinical presentation. At follow-up, clinical outcomes were assessed in terms of transition or nontransition to psychosis using the Comprehensive Assessment of the At-Risk Mental State criteria and the level of overall functioning using the Global Assessment of Function scale. Results: Of 116 total participants, 86 were at clinical high risk for psychosis (50 [58%] male; mean [SD] age, 22.4 [3.5] years) and 30 were healthy controls (14 [47%] male; mean [SD] age, 24.7 [3.8] years). At follow-up, 12 clinical high-risk individuals developed a first episode of psychosis whereas 74 clinical high-risk individuals did not; 19 clinical high-risk individuals showed good overall functioning (Global Assessment of Function ≥65), whereas 38 clinical high-risk individuals had a poor functional outcome (Global Assessment of Function <65). Compared with clinical high-risk individuals who did not become psychotic, clinical high-risk individuals who developed psychosis showed higher hippocampal glutamate levels (mean [SD], 8.33 [1.48] vs 9.16 [1.28] glutamate levels; P = .048). The clinical high-risk individuals who developed psychosis also had higher myo-inositol levels (mean [SD], 7.60 [1.23] vs 6.24 [1.36] myo-inositol levels; P = .002) and higher creatine levels (mean [SD], 8.18 [0.74] vs 7.32 [1.09] creatine levels; P = .01) compared with clinical high-risk individuals who did not become psychotic, and higher myo-inositol levels compared with healthy controls (mean [SD], 7.60 [1.23] vs 6.19 [1.51] myo-inositol levels; P = .005). Higher hippocampal glutamate levels in clinical high-risk individuals were also associated with a poor functional outcome (mean [SD], 8.83 [1.43] vs 7.76 [1.40] glutamate levels; P = .02). In the logistic regression analyses, hippocampal glutamate levels were significantly associated with clinical outcome in terms of transition and nontransition to psychosis (ß = 0.48; odds ratio = 1.61; 95% CI, 1.00-2.59; P = .05) and overall functioning (ß = 0.53; odds ratio = 1.71; 95% CI, 1.10-2.66; P = .02). Conclusions and Relevance: The findings indicate that adverse clinical outcomes in individuals at clinical high risk for psychosis may be associated with an increase in baseline hippocampal glutamate levels, as well as an increase in myo-inositol and creatine levels. This conclusion suggests that these measures could contribute to the stratification of clinical high-risk individuals according to future clinical outcomes.

Childhood Trauma and Neurocognition in Adults With Psychotic Disorders: A Systematic Review and Meta-analysis.

BACKGROUND: Characterizing the link between childhood trauma and adult neurocognitive function in psychosis is crucial for improving the fields understanding of how early environmental risk factors impact the presentation of the disorder. To date, the literature has been inconsistent: meta-analytic synthesis is lacking, and it is unclear whether specific cognitive functions are affected. METHODS: A meta-analysis was performed on a total of 3315 subjects with a psychotic disorder. The links between childhood trauma, overall neurocognitive function, and four cognitive subdomains (working memory, executive function, verbal/visual memory, and attention/processing speed) were examined. Relevant sample characteristics and methodological moderators were tested. The strength of the association between trauma and overall neurocognition in individuals with psychotic disorders was also compared to that of healthy controls. RESULTS: Among individuals with psychotic disorders, there was a significant association between overall cognition and childhood trauma, r = -.055; 95% CI = -0.09, -0.02, P = .002. There was also a modest, negative relationship between childhood trauma and working memory, r = -.091; 95% CI = -0.15, -0.03, P = .002. Moderators did not have a significant effect on these analyses. Further, the association between childhood trauma and neurocognition was significantly stronger in healthy controls compared to patients with a psychotic disorder. CONCLUSION: A small negative association was found between overall cognition and childhood trauma in individuals with psychotic disorders. Results suggest the association is less strong for individuals with a psychotic disorder compared to healthy populations. Findings are informative for prominent etiological models of psychosis.

Factor Analysis of Negative Symptom Items in the Structured Interview for Prodromal Syndromes.

BACKGROUND: Negative symptoms occur early in the clinical high risk (CHR) state and indicate increased risk of conversion to psychotic disorder and poor functional outcome. However, while the negative symptom domain has shown to be parsimoniously explained by a 2-factor construct in schizophrenia, there has yet to be an established factor structure of negative symptoms in CHR. METHODS: 214 individuals meeting the Structured Interview for Psychosis-Risk Syndromes (SIPS) criteria for CHR were recruited through 3 active research programs in the United States. Exploratory Factor Analysis was conducted on the 6 negative symptom items of the SIPS, and factors were evaluated with respect to functional outcome and depression. RESULTS: Factor analysis indicated a 2-factor hierarchical model with 2 negative symptom dimensions reflecting volition (Occupational Functioning and Avolition) and emotion (Expression of Emotion, Experience of Emotion and Social Anhedonia). Linear Regression showed that the emotion factor was associated with poor social function, and the volition factor was associated with poor role function and depression. CONCLUSIONS: Similar to factor solutions identified in adults diagnosed with psychotic disorders, results indicated that the SIPS negative symptom subscale is not a unidimensional construct. Rather, the SIPS negative subscale has 2 distinct factors that have different associations with clinical outcome and should be interpreted independently. Results have significant relevance for informing the valid assessment and conceptual interpretation of early clinical phenomenology in the psychosis prodrome.

Correction: Prefrontal GABA levels, hippocampal resting perfusion and the risk of psychosis.

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Prefrontal GABA levels, hippocampal resting perfusion and the risk of psychosis.

Preclinical models propose that the onset of psychosis is associated with hippocampal hyperactivity, thought to be driven by cortical GABAergic interneuron dysfunction and disinhibition of pyramidal neurons. Recent neuroimaging studies suggest that resting hippocampal perfusion is increased in subjects at ultra-high risk (UHR) for psychosis, but how this may be related to GABA concentrations is unknown. The present study used a multimodal neuroimaging approach to address this issue in UHR subjects. Proton magnetic resonance spectroscopy and pulsed-continuous arterial spin labeling imaging were acquired to investigate the relationship between medial prefrontal (MPFC) GABA+ levels (including some contribution from macromolecules) and hippocampal regional cerebral blood flow (rCBF) in 36 individuals at UHR of psychosis, based on preclinical evidence that MPFC dysfunction is involved in hippocampal hyperactivity. The subjects were then clinically monitored for 2 years: during this period, 7 developed a psychotic disorder and 29 did not. At baseline, MPFC GABA+ levels were positively correlated with rCBF in the left hippocampus (region of interest analysis, p = 0.044 family-wise error corrected, FWE). This correlation in the left hippocampus was significantly different in UHR subjects who went on to develop psychosis relative to those who did not (p = 0.022 FWE), suggesting the absence of a correlation in the latter subgroup. These findings provide the first human evidence that MPFC GABA+ concentrations are related to resting hippocampal perfusion in the UHR state, and offer some support for a link between GABA levels and hippocampal function in the development of psychosis.

Increased Resting Hippocampal and Basal Ganglia Perfusion in People at Ultra High Risk for Psychosis: Replication in a Second Cohort.

We recently reported that resting hippocampal, basal ganglia and midbrain perfusion is elevated in people at ultra high risk (UHR) for psychosis. The present study sought to replicate our previous finding in an independent UHR cohort, and examined the relationship between resting perfusion in these regions, psychosis and depression symptoms, and traumatic experiences in childhood. Pseudo-Continuous Arterial Spin Labelling (p-CASL) imaging was used to measure resting cerebral blood flow (rCBF) in 77 UHR for psychosis individuals and 25 healthy volunteers in a case-control design. UHR participants were recruited from clinical early detection services at 3 sites in the South of England. Symptoms levels were assessed using the Comprehensive Assessment of At Risk Mental States (CAARMS), the Hamilton Depression Scale (HAM-D), and childhood trauma was assessed retrospectively using the Childhood Trauma Questionnaire (CTQ). Right hippocampal and basal ganglia rCBF were significantly increased in UHR subjects compared to controls, partially replicating our previous finding in an independent cohort. In UHR participants, positive symptoms were positively correlated with rCBF in the right pallidum. CTQ scores were positively correlated with rCBF values in the bilateral hippocampus and negatively associated with rCBF in the left prefrontal cortex. Elevated resting hippocampal and basal ganglia activity appears to be a consistent finding in individuals at high risk for psychosis, consistent with data from preclinical models of the disorder. The association with childhood trauma suggests that its influence on the risk of psychosis may be mediated through an effect on hippocampal function.

Cortical GABA in Subjects at Ultra-High Risk of Psychosis: Relationship to Negative Prodromal Symptoms.

Background: Whilst robust preclinical and postmortem evidence suggests that altered GABAergic function is central to the development of psychosis, little is known about whether it is altered in subjects at ultra-high risk of psychosis, or its relationship to prodromal symptoms. Methods: Twenty-one antipsychotic naïve ultra-high risk individuals and 20 healthy volunteers underwent proton magnetic resonance imaging at 3T. Gamma-aminobutyric acid levels were obtained from the medial prefrontal cortex using MEGA-PRESS and expressed as peak-area ratios relative to the synchronously acquired creatine signal. Gamma-aminobutyric acid levels were then related to severity of positive and negative symptoms as measured with the Community Assessment of At-Risk Mental States. Results: Whilst we found no significant difference in gamma-aminobutyric acid levels between ultra-high risk subjects and healthy controls (P=.130), in ultra-high risk individuals, medial prefrontal cortex GABA levels were negatively correlated with the severity of negative symptoms (P=.013). Conclusion: These findings suggest that gamma-aminobutyric acidergic neurotransmission may be involved in the neurobiology of negative symptoms in the ultra-high risk state.