Ultra-high Risk Samples Research Articles

Overlooking the transition elephant in the ultra-high-risk room: are we missing functional equivalents of transition to psychosis?

In the wake of the almost quarter of a century since the conceptualization of ultra-high-risk (UHR) states for psychosis, empirical evidences in the field are constantly scrutinized and re-assessed through meta-analytic lens. Briefly, such scrutiny converges on three major evidences: pretest risk enrichment, risk hierarchy within UHR states, and declining transition rates. While the former two are intuitive, the dilution effect remains elusive and might be rather symptomatic of unsolved issues in the field. Those include the heterogeneously reported antipsychotic (AP) exposure in UHR samples and the almost univocal focus on purely psychometric transition to psychosis. Both issues lead to the neglect of functional equivalents of transition, i.e. that of a mental state at immediate need for AP medication, and might have a cascading confounding effect on the predictive value of contemporary risk calculators centered on criterial transition as a unique outcome.

Latent profile analysis of psychosis liability in a community-derived sample of adolescents: Links with mental health difficulties, suicidal ideation, bipolar-like experiences and psychotic-like experiences.

The main goal of the present study was to explore the latent structure of schizotypy as an indicator of psychosis liability, in a community-derived sample of adolescents. Links to mental health difficulties, prosocial behaviour, suicidal ideation, bipolar-like experiences and psychotic-like experiences (PLEs) (severity and distress) were compared across schizotypy latent profiles. The present research included 1588 adolescents selected by a stratified random cluster sampling. The Oviedo Schizotypy Assessment Questionnaire (ESQUIZO-Q), The Paykel Suicide Scale (PSS), The Strengths and Difficulties Questionnaire (SDQ), The Prodromal Questionnaire-Brief (PQ-B), The Mood Disorder Questionnaire (MDQ), The Penn Matrix Reasoning Test (PMRT), The Family Affluence Scale-II (FAS-II), and The Oviedo Infrequency Scale (INF-OV) were used. Using latent profile analysis four latent classes (LC) were identified: "Positive schizotypy" (14.1%, n = 224), "Low schizotypy" (51.9%, n = 825), "Social Disorganization schizotypy" (27.2%, n = 432), and "High schizotypy" (6.7%, n = 107). The "High schizotypy" class scored higher on several psychometric indicators of psychopathology (ie, mental health difficulties, suicide ideation, bipolar-like experiences and PLEs) relative to the other three LC. Four groups of adolescents with different patterns of schizotypal traits and different clinical-pathological meaning were found. Deficits found across schizotypy latent profiles, resembling those found in patients with psychosis and ultra-high risk samples. The identification of homogeneous subgroups of adolescents potentially at risk for psychosis may help us in the prevention of psychotic-spectrum disorders and mental health problems.

T174. STRUCTURAL ABNORMALITIES IN THE CINGULATE CORTEX IN ADOLESCENTS AT ULTRA-HIGH RISK WHO LATER DEVELOP PSYCHOSIS

BackgroundIdentification of biomarkers of transition to psychosis in individuals at ultra-high risk (UHR) has the potential to improve future outcomes (McGorry, 2008). Structural MRI studies with UHR samples have revealed steeper rates of cortical thinning in temporal, prefrontal and cingulate cortices in individuals who later develop psychosis in both baseline and longitudinal comparisons (Fusar-Poli, 2011; Cannon, 2014). However, little is known about how onset of prodromal symptoms during adolescence impacts on changes in cortical thickness (CTH) (Ziermans, 2012).MethodsMulticentre cross-sectional case-control study, including youth aged 10–17 years, recruited from two child and adolescent mental health centres. UHR individuals were identified using the Structured Interview for Prodromal Syndromes criteria with some modifications. Healthy controls (HC) were recruited from the same geographical area. Exclusion criteria comprised personal history of psychotic symptoms, IQ<70, autism spectrum disorder, presence of neurological disorder, or antecedents of head trauma with loss of consciousness. The study was approved by the local Ethical Review Boards. All participants underwent a comprehensive socio-demographic and clinical evaluation at baseline and after 6, 12 and 18 months follow-up to identify which individuals converted to psychosis (UHR-P) and which did not (UHR-NP).High-resolution magnetic resonance structural images were acquired at baseline on a 3Tesla and 1.5Tesla scanners. An inter-site compatibility study was conducted with healthy controls which revealed high inter-site correlation coefficients (r>.6) for CTH measures. Images were pre-processed employing automated procedures implemented in FreeSurfer 5.3.0, cortical parcellation employed the Desikan-Killiany brain atlas. Analyses: First, mean global and lobar (frontal, parietal, temporal, occipital, insula and cingulate) CTH measurements were computed. Then, within lobes showing group effects, CTH was measured for each parcellation. ANCOVA was performed to test differences between groups in SPSS 22.0, including gender, age, total intracranial volume and site as covariates. Significance was set at p<.05, corrected using the false discovery rate (FDR).Results122 subjects were included (59 UHR-NP vs. 18 UHR-P vs. 45 HC, mean ages: 15.2 ± 1.5 vs. 15.0 ± 1.8 vs. 15.8 ± 1.5, F=1.9, p=.15; gender (%female): 61.0% vs 61.1% vs 68.9%, χ2=.76, p=.68). There were no significant differences in case-control proportion between centres: χ2=1.3, p=.25. No significant differences in global CTH in UHR-P (2.57 ± 0.13mm) relative to UHR-NP (2.56 ± 0.11mm) and HC (2.58 ± 0.09mm) were found.There was a significant group effect on the right cingulate cortex (F=6.6, pFDR=.024): UHR-P showed lower CTH in this area relative to controls (p=.007 uncorrected). Within the right cingulate cortex, a significant group effect was found in the posterior cingulate (F=5.7, pFDR=.016) and isthmus (F=4.6, pFDR=.024), and a trend level in the caudal anterior cingulate (F=2.9, p=.057): with smaller CTH in UHR-P relative to HC in the isthmus cingulate (p=.025) and the posterior cingulate (p=.066). No significant differences were observed between UHR-P and UHR-NP groups.DiscussionUHR-P showed significant cortical thinning in several regions of the right cingulate cortex in comparison to HC, giving support to the notion that structural alterations in the cingulate cortex may be present in children and adolescents prior the onset of psychosis. Longitudinal changes in CTH have the potential to increase understanding of changes related to transition to clinical illness.

White matter integrity in individuals at ultra-high risk for psychosis: a systematic review and discussion of the role of polyunsaturated fatty acids.

BackgroundSchizophrenia is thought to be a neurodevelopmental disorder with pathophysiological processes beginning in the brain prior to the emergence of clinical symptoms. Recent evidence from neuroimaging studies using techniques such as diffusion tensor imaging has identified white matter abnormalities that are suggestive of disrupted brain myelination and neuronal connectivity. Identifying whether such effects exist in individuals at high risk for developing psychosis may help with prevention and early intervention strategies. In addition, there is preliminary evidence for a role of lipid biology in the onset of psychosis, along with well-established evidence of its role in myelination of white matter tracts. As such, this article synthesises the literature on polyunsaturated fatty acids (PUFAs) in myelination and schizophrenia, hypothesizing that white matter abnormalities may potentially mediate the relationship between PUFAs and schizophrenia.MethodsDiffusion tensor imaging studies were identified through a systematic search of existing literature. Studies examined white matter integrity in ultra-high risk (UHR) samples, as assessed using structured diagnostic interviews. Data was extracted and summarised as a narrative review.ResultsTwelve studies met inclusion criteria, and findings identified reduced fractional anisotropy and higher diffusivity. Although the exact location of abnormalities remains uncertain, fronto-temporal and fronto-limbic connections, including the superior longitudinal and uncinate fasiculus, cingulum, and corpus callosum appear to be implicated. Because of preliminary evidence suggesting lipid biology may be relevant for the onset of psychosis, a discussion is provided of the role of polyunsaturated fatty acids (PUFAs) in myelination and risk for psychosis.ConclusionsWhile the function of PUFAs in myelination is well-established, there is growing evidence of reduced PUFA concentration in UHR samples, highlighting the need for research to examine the relationship between PUFA and white matter integrity in high-risk samples and age-matched healthy controls. Such investigations will help to better understand the pathophysiology of the disorder, and potentially assist in the development of novel treatment and early intervention strategies.

Distress in relation to attenuated psychotic symptoms in the ultra-high-risk population is not associated with increased risk of psychotic disorder.

The 'ultra-high-risk' criteria identify a clinical population at substantially increased risk for progressing to schizophrenia and other psychotic disorders. Although a number of clinical variables predictive of transition to psychotic disorder have been identified within this population, the predictive value of the level of distress associated with attenuated psychotic symptoms has not yet been examined. This was the aim of the present study. The level of distress (0-100) associated with attenuated psychotic symptoms was recorded for 70 ultra-high-risk (UHR) patients using the Comprehensive Assessment of At-Risk Mental State (CAARMS). Transition to psychosis was assessed over a 16-month follow-up period. Of the 70 UHR patients, 15 transitioned to psychosis (21.4%). Of the four CAARMS subscales measuring attenuated positive symptoms, Perceptual Abnormalities was rated as the most distressing. There were no differences in CAARMS scales rated as the most distressing between those who transitioned to psychosis and those who did not. There was also no association between higher levels of distress associated with attenuated psychotic symptoms and transition to psychosis. Although the findings require replication, they indicate that the degree of distress associated with attenuated psychotic symptoms should not be used as a criterion for enriching UHR samples for risk of frank psychotic disorder.

Early intervention in psychosis: a feasibility study financed by the Italian Center on Control of Maladies

In November 2005 the Italian Center on Control of Maladies, a department operating under the Ministry of Health, financed a project aimed at evaluating the feasibility of a protocol of intervention based on the early intervention in psychosis (EIP) model within the Italian public mental health-care network. The study was carried out between March 2007 and December 2009. It involved five centres operating under the Departments of Mental Health of Milan (Programma 2000), Rome (area D), Grosseto, Salerno (Nocera) and Catanzaro (Soverato). Enrolment lasted 12 months, at the end of which 43 patients were enrolled as first-episode psychosis (FEP), and 24 subjects as ultra high-risk (UHR) patients. Both FEP and UHR samples included a preponderance of male patients. A family history of psychosis was rarely reported in both samples. The FEP incidence rate was lower than expected on the basis of international estimates of the incidence of schizophrenia but within the expected figure for the estimated Italian rates in three centres out of five. Overall, the study proved that an EIP centre can be established within the public Department of Mental Health to reach a good fraction of the cases in need of treatment. Since then, several studies have been set up to assess the feasibility of EIP in the Italian public mental health sector in Lombardy and Tuscany, and in 2012 the Emilia-Romagna Regional Authority started an educational plan aimed at implementing the EIP model in all the Mental Health Departments in the region.

Figural fluency and immediate visual memory in patients with at-risk mental state for psychosis: empirical study

Although a number of cognitive functions have been assessed in the ultra-high risk (UHR) population, only one study has reported on figural fluency. Visual memory was measured by different tests providing inconsistent results. The aim of the present study was to compare figural fluency and visual immediate memory performance in UHR patients and normal subjects. The UHR sample consisted of 55 help-seeking individuals meeting CAARMS criteria. The control group consisted of 65 subjects. They were matched as a group by age, gender and education level. Figural fluency (RFFT) and immediate visual memory (BVRT) were assessed within 2 weeks after inclusion in the study in the UHR patient group. Significant differences were obtained in RFFT and BVRT results. In BVRT, UHR patients scored lower in number of correct designs (P < 0.001) and higher in number of errors (P < 0.0001), especially omissions (P < 0.001) and distortions (P < 0.0001). UHR subjects accurately recalled fewer designs, omitted and distorted more test figures. In RFFT, they scored lower in production of novel designs (P < 0.0001) and higher in the error ratio index (P < 0.008). They produced fewer novel designs and made more preservative errors. The current study concerns non-verbal cognitive functions in UHR samples. Our results suggest that figural fluency and visual immediate memory are impaired in help-seeking UHR individuals as compared with matched controls.

14:15 PERSISTENCE OF THE EXTENDED PSYCHOSIS PHENOTYPE IN YOUNG PEOPLE: LINK BETWEEN VULNERABILITY AND CLINICAL NEED

Psychosis is one of the most severe psychiatric conditions, in terms of both individual and societal burden. The pathway from the earliest and mildest expressions of psychosis to clinical disorder is highly variable and heterogeneous. A better understanding of the psychosis phenotype and its development into clinical states is important, since this offers opportunities for early intervention of psychotic disorders, with the ultimate goal to delay, attenuate or even prevent transition to clinical disorder. Psychosis is currently conceptualized as an extended, or continuous, phenotype, ranging from normal functioning at one end, through eccentricity and subclinical psychotic experiences, to florid psychotic disorder at the other end. The manifestation of this (liability to) psychotic psychopathology is represented by a continuous distribution of psychotic symptom severity/intensity in the general population. The studies in this thesis showed that many adolescents reported incidental subclinical psychotic experiences, underlining the high level of psychosis proneness in this developmental life phase. This psychosis proneness decreased with age, demonstrated by the lower levels of psychotic experiences reported by the young adult female sample compared to the adolescent samples. A model with five subdimensions, labeled Hallucinations, Delusions, Paranoia, Grandiosity and Paranormal beliefs, was shown to describe these experiences well in two large adolescent samples from the general population and was furthermore replicated in young adulthood, suggesting life-long stability of this underlying structure. Only some of these subdimensions (i.e. Hallucinations, Delusions and Paranoia) may tap into the extended psychosis phenotype in their continuity with mental illness. Psychosis proneness was shown to be very dynamic, particularly during adolescence. Many (biological, psychological and sociological) factors play a role in its development, such as trauma, cannabis use, depression, coping and genetic liability for psychosis; thus, it demonstrates that the development of psychosis over time takes place in a developmental and psychopathological context. Subclinical psychotic experiences are thought to be predictive for later clinical psychosis, as is, more strongly, Ultra High Risk (UHR) status. In other words, it is assumed that there is a dose-response function of risk between psychotic experiences/symptoms and later psychotic disorder. There is, however, a gap in the conceptualization of the psychosis continuum between subclinical psychosis at the level of the general population and UHR status for psychosis: there is no clear phenotype on the hypothesized psychosis continuum connecting individuals from the general population and individuals who are seeking help for their psychotic experiences. Studying the persistence of subclinical psychotic experiences over time may form the bridge between general population samples and UHR samples in the study of (the development of) psychosis, because this paradigm offers the possibility to study the extended psychosis phenotype at the level of the general population while focusing on a more specific phenotype that may be indicative for later psychotic development. Studying this phenotype of persisting subclinical psychotic experiences that can be seen as intermediate between general population and clinical population may thus be a fruitful paradigm for identifying individuals at increased risk for the development of psychosis.

The Phenomenological Critique and Self-disturbance: Implications for Ultra-High Risk ("Prodrome") Research

Recent years have witnessed widespread interest in the early phase of schizophrenia and other psychotic disorders. Strategies have been introduced to attempt to identify individuals in the prepsychotic or prodromal phase. The most widely used of these approaches is the ultra-high risk (UHR) approach, which combines known trait and state risk factors for psychotic disorder. However, researchers guided by phenomenological theory have argued that modern psychiatry's neglect of subjective experience has compromised researchers' understanding of psychotic disorder and has thereby limited efforts at prospective and early identification. Phenomenological research indicates that disturbance of the basic sense of self may be a core marker of psychotic vulnerability, particularly of schizophrenia spectrum disorders. It is argued that identifying self-disturbance in the UHR population may provide a means of further "closing in" on individuals truly at high risk of psychotic disorder, thus supplementing the UHR identification approach. This would be of practical value in the sense of reducing inclusion of "false-positive" cases in UHR samples and of theoretical value in the sense of shedding light on core features of psychotic pathology. The strong explanatory power and empirical findings to date invite further research into the role of self-disturbance as a phenotypic vulnerability marker for psychotic disorder.