A.R. Yung

Neurocognitive predictors of functional outcome two to 13 years after identification as ultra-high risk for psychosis

BACKGROUND AND AIMnLittle is known about the relationship between neurocognitive performance and functional outcome before the onset of frank psychosis. This longitudinal study aimed to investigate neurocognitive predictors of poor functional outcome in a group identified as ultra-high risk (UHR) for psychosis between two and 13 years prior.nnnMETHODnIndividuals (N=230) identified as UHR for psychosis at the PACE Clinic in Melbourne completed assessment of psychopathology, functioning and neurocognition at baseline and follow-up. The mean length of follow-up was 7.26 years (SD 3.05).nnnRESULTSnForty-one individuals with the poorest functional outcome were identified. Only 48.8% of this group had transitioned to psychosis. Poor functional outcome was associated with reduced performance at baseline in the specific neurocognitive domains of verbal learning and memory, processing speed and attention, and verbal fluency, but not global cognitive impairment. Reduced performance on a verbal story recall task, in combination with higher negative symptoms at baseline, was the best predictor of later poor outcome. Baseline positive psychotic symptoms and GAF scores were not associated with later poor outcome.nnnDISCUSSIONnTo date, this is the longest follow-up study of an UHR sample. Poor functional outcome was associated with specific neurocognitive decrements, regardless of transition to psychosis. The detection of individuals with poor functioning at follow-up, against a background of previously identified risk factors for psychotic disorder, may yield a valid group in which to study biomarkers and treatment of schizophrenia.

Road to full recovery: Longitudinal relationship between symptomatic remission and psychosocial recovery in first-episode psychosis over 7.5 years

BACKGROUNDnIn recent years there has been increasing interest in functional recovery in the early phase of schizophrenia. Concurrently, new remission criteria have been proposed and several studies have examined their clinical relevance for prediction of functional outcome in first-episode psychosis (FEP). However, the longitudinal interrelationship between full functional recovery (FFR) and symptom remission has not yet been investigated. This study sought to: (1) examine the relationships between FFR and symptom remission in FEP over 7.5 years; (2) test two different models of the interaction between both variables.nnnMETHODnAltogether, 209 FEP patients treated at a specialized early psychosis service were assessed at baseline, 8 months, 14 months and 7.5 years to determine their remission of positive and negative symptoms and functional recovery. Multivariate logistic regression and path analysis were employed to test the hypothesized relationships between symptom remission and FFR.nnnRESULTSnRemission of both positive and negative symptoms at 8-month follow-up predicted functional recovery at 14-month follow-up, but had limited value for the prediction of FFR at 7.5 years. Functional recovery at 14-month follow-up significantly predicted both FFR and remission of negative symptoms at 7.5 years, irrespective of whether remission criteria were simultaneously met. The association remained significant after controlling for baseline prognostic indicators.nnnCONCLUSIONSnThese findings provided support for the hypothesis that early functional and vocational recovery plays a pivotal role in preventing the development of chronic negative symptoms and disability. This underlines the need for interventions that specifically address early psychosocial recovery.

Mapping the onset of psychosis: The comprehensive assessment of at risk mental states (CAARMS)

OBJECTIVEnRecognizing the prodrome of a first psychotic episode prospectively creates the opportunity of intervention, which could delay, ameliorate or even prevent onset. Valid criteria and a reliable methodology for identifying possible prodromes are needed. This paper describes an instrument, the Comprehensive Assessment of At-Risk Mental States (CAARMS), which has been designed for such a purpose. It has two functions: (i) to assess psychopathology thought to indicate imminent development of a first-episode psychotic disorder; and (ii) to determine if an individual meets criteria for being at ultra high risk (UHR) for onset of first psychotic disorder. This paper describes the pilot evaluation of the CAARMS.nnnMETHODnSeveral methodologies were used to test the CAARMS. First, CAARMS scores in a group of UHR young people and the association between CAARMS scores and the risk of transition to psychotic disorder, were analysed. Second, CAARMS scores in a UHR group were compared to a control group. To assess concurrent validity, CAARMS-defined UHR criteria were compared to the existing criteria for identifying the UHR cohort. To assess predictive validity, the CAARMS-defined UHR criteria were applied to a sample of 150 non-psychotic help-seekers and rates of onset of psychotic disorder at 6-month follow-up determined for the CAARMS-positive (i.e. met UHR criteria) group and the CAARMS-negative (i.e. did not meet UHR criteria) group. The inter-rater reliability of the CAARMS was assessed by using pairs of raters.nnnRESULTSnHigh CAARMS score in the UHR group was significantly associated with onset of psychotic disorder. The control group had significantly lower CAARMS scores than the UHR group. The UHR criteria assessed by the CAARMS identified a similar group to the criteria measured by existing methodology. In the sample of non-psychotic help-seekers those who were CAARMS-positive were at significantly increased risk of onset of psychotic disorder compared to those who were CAARMS-negative (relative risk of 12.44 (95% CI = 1.5-103.41, p = 0.0025)). The CAARMS had good to excellent reliability.nnnCONCLUSIONSnIn these preliminary investigations, the CAARMS displayed good to excellent concurrent, discriminant and predictive validity and excellent inter-rater reliability. The CAARMS instrument provides a useful platform for monitoring subthreshold psychotic symptoms for worsening into full-threshold psychotic disorder.

Negative psychotic symptoms and impaired role functioning predict transition outcomes in the at-risk mental state: a latent class cluster analysis study

BACKGROUNDnMany research groups have attempted to predict which individuals with an at-risk mental state (ARMS) for psychosis will later develop a psychotic disorder. However, it is difficult to predict the course and outcome based on individual symptoms scores.nnnMETHODnData from 318 ARMS individuals from two specialized services for ARMS subjects were analysed using latent class cluster analysis (LCCA). The score on the Comprehensive Assessment of At-Risk Mental States (CAARMS) was used to explore the number, size and symptom profiles of latent classes.nnnRESULTSnLCCA produced four high-risk classes, censored after 2 years of follow-up: class 1 (mild) had the lowest transition risk (4.9%). Subjects in this group had the lowest scores on all the CAARMS items, they were younger, more likely to be students and had the highest Global Assessment of Functioning (GAF) score. Subjects in class 2 (moderate) had a transition risk of 10.9%, scored moderately on all CAARMS items and were more likely to be in employment. Those in class 3 (moderate-severe) had a transition risk of 11.4% and scored moderately severe on the CAARMS. Subjects in class 4 (severe) had the highest transition risk (41.2%), they scored highest on the CAARMS, had the lowest GAF score and were more likely to be unemployed. Overall, class 4 was best distinguished from the other classes on the alogia, avolition/apathy, anhedonia, social isolation and impaired role functioning.nnnCONCLUSIONSnThe different classes of symptoms were associated with significant differences in the risk of transition at 2 years of follow-up. Symptomatic clustering predicts prognosis better than individual symptoms.

The relationship between coping and subclinical psychotic experiences in adolescents from the general population – a longitudinal study

BACKGROUNDnSubclinical psychotic experiences during adolescence may represent liability for developing psychotic disorder. Both coping style and the degree of persistence of psychotic experiences may play a role in the progression to clinical psychotic disorder, but little is known about the causal relationship between the two.nnnMETHODnPath modelling was used to examine longitudinal relationships between subclinical positive psychotic experiences and three styles of coping (task-, emotion- and avoidance-oriented) in an adolescent general population sample (n=813) assessed three times in 3 years. Distinct developmental trajectories of psychotic experiences, identified with growth mixture modelling, were compared on the use of these coping styles.nnnRESULTSnOver time, emotion-oriented coping in general was bi-directionally related to psychotic experiences. No meaningful results were found for task- or avoidance-oriented coping. Females reported using a wider range of coping styles than males, but the paths between coping and psychotic experiences did not differ by gender. Persistence of psychotic experiences was associated with a greater use of emotion-oriented coping, whereas a decrease in experiences over time was associated with an increased use of task-orientated coping.nnnCONCLUSIONSnEmotion-oriented coping is the most important coping style in relation to psychotic experiences, as it may contribute to a vicious cycle and is associated with persistence of experiences. In addition, more task-oriented coping may result in a decrease in psychotic experiences. Results suggest that opportunities for intervention may already be present at the level of subclinical psychosis.

Subclinical psychosis and depression: Co-occurring phenomena that do not predict each other over time

BACKGROUNDnThe path from subclinical psychotic experiences to clinical disorder is thought to be mediated by the persistence of subclinical psychotic experiences. One of the factors that is likely associated with this persistence is depression. Although commonly viewed as interrelated concepts, the exact relationship between subclinical psychosis and depression is not clear.nnnMETHODSnCross-lagged path modeling was used to explore the relationship between subclinical psychosis and depression across and over time in an adolescent population seeking assistance for non-psychotic disorders (N=138), measured at four occasions over a two-year period.nnnRESULTSnSubclinical psychosis and depression were related to each other at every cross-sectional measurement, but did not predict each other over time. Subclinical psychotic experiences and depressive symptom levels were highest at baseline, when participants presented to the clinical service for help. In addition, the relationship between them was also strongest at baseline and decreased significantly over time.nnnCONCLUSIONnThe results suggest that psychosis and depression are interrelated phenomena that strongly co-occur in time, but longitudinally, one does not predict change in the other. Both psychopathological dimensions should be addressed when treatment is provided to adolescent help-seekers.

Neurocognitive predictors of transition to psychosis: medium- to long-term findings from a sample at ultra-high risk for psychosis

BACKGROUNDnIndividuals at ultra-high risk (UHR) for psychosis show reduced neurocognitive performance across domains but it is unclear which reductions are associated with transition to frank psychosis. The aim of this study was to investigate differences in baseline neurocognitive performance between UHR participants with (UHR-P) and without transition to psychosis (UHR-NP) and a healthy control (HC) group and examine neurocognitive predictors of transition over the medium to long term.nnnMETHODnA sample of 325 UHR participants recruited consecutively from the Personal Assessment and Crisis Evaluation (PACE) Clinic in Melbourne and 66 HCs completed a neurocognitive assessment at baseline. The UHR group was followed up between 2.39 and 14.86 (median = 6.45) years later. Cox regression was used to investigate candidate neurocognitive predictors of psychosis onset.nnnRESULTSnThe UHR group performed more poorly than the HC group across a range of neurocognitive domains but only performance on digit symbol coding and picture completion differed between the groups. The risk of transition was only significantly associated with poorer performance on visual reproduction [hazard ratio (HR) 0.919, 95% confidence interval (CI) 0.876-0.965, p = 0.001] and matrix reasoning (HR 0.938, 95% CI 0.883-0.996, p = 0.037). These remained significant even after controlling for psychopathology at baseline.nnnCONCLUSIONSnThis study is the longest follow-up of an UHR sample to date. UHR status was associated with poorer neurocognitive performance compared to HCs on some tasks. Cognition at identification as UHR was not a strong predictor of risk for transition to psychosis. The results suggests the need to include more experimental paradigms that isolate discrete cognitive processes to better understand neurocognition at this early stage of illness.

Reduced parahippocampal cortical thickness in subjects at ultra-high risk for psychosis

Background Grey matter volume and cortical thickness represent two complementary aspects of brain structure. Several studies have described reductions in grey matter volume in people at ultra-high risk (UHR) of psychosis; however, little is known about cortical thickness in this group. The aim of the present study was to investigate cortical thickness alterations in UHR subjects and compare individuals who subsequently did and did not develop psychosis. Method We examined magnetic resonance imaging data collected at four different scanning sites. The UHR subjects were followed up for at least 2 years. Subsequent to scanning, 50 UHR subjects developed psychosis and 117 did not. Cortical thickness was examined in regions previously identified as sites of neuroanatomical alterations in UHR subjects, using voxel-based cortical thickness. Results At baseline UHR subjects, compared with controls, showed reduced cortical thickness in the right parahippocampal gyrus (p < 0.05, familywise error corrected). There were no significant differences in cortical thickness between the UHR subjects who later developed psychosis and those who did not. Conclusions These data suggest that UHR symptomatology is characterized by alterations in the thickness of the medial temporal cortex. We did not find evidence that the later progression to psychosis was linked to additional alterations in cortical thickness, although we cannot exclude the possibility that the study lacked sufficient power to detect such differences.

Effects of NRG1 and DAOA genetic variation on transition to psychosis in individuals at ultra-high risk for psychosis

Prospective studies have suggested genetic variation in the neuregulin 1 (NRG1) and D-amino-acid oxidase activator (DAOA) genes may assist in differentiating high-risk individuals who will or will not transition to psychosis. In a prospective cohort (follow-up=2.4–14.9 years) of 225 individuals at ultra-high risk (UHR) for psychosis, we assessed haplotype-tagging single-nucleotide polymorphisms (htSNPs) spanning NRG1 and DAOA for their association with transition to psychosis, using Cox regression analysis. Two NRG1 htSNPs (rs12155594 and rs4281084) predicted transition to psychosis. Carriers of the rs12155594 T/T or T/C genotype had a 2.34 (95% confidence interval (CI)=1.37–4.00) times greater risk of transition compared with C/C carriers. For every rs4281084 A-allele the risk of transition increased by 1.55 (95% CI=1.05–2.27). For every additional rs4281084-A and/or rs12155594-T allele carried the risk increased ∼1.5-fold, with 71.4% of those carrying a combination of ⩾3 of these alleles transitioning to psychosis. None of the assessed DAOA htSNPs were associated with transition. Our findings suggest NRG1 genetic variation may improve our ability to identify UHR individuals at risk for transition to psychosis.

Can We Detect Psychotic-like Experiences in the General Population?

The continuum model of psychosis posits that psychotic symptoms are distributed throughout the population, with diagnosable clinical disorder existing at a certain point along this continuum. The total continuum is made up mainly of non-clinical cases with clinical cases of psychosis representing only a small proportion of the total extended psychosis phenotype. This paper is a narrative review of studies of psychotic experiences in the general population. The evidence indicates reasonably high prevalence rates of psychotic experiences in the general population, substantially higher than the prevalence of psychotic disorders, and that they are associated with increased risk of future onset of diagnosable disorder, particularly when the experiences are persistent. Psychotic experiences in the general population share an extensive range of risk factors with schizophrenia and therefore provide a useful phenotype in which to study the aetiology of clinical psychosis. Some types of psychotic experiences, such as paranoid ideas, bizarre thinking and perceptual abnormalities, may indicate a greater level of risk for psychotic disorder than other psychotic experiences, such as magical thinking. There is a need for research that further explores the interplay between psychotic experiences and other risk factors (including psychological, environmental, neurocognitive and genetic factors) in the evolution of psychotic disorder, the types of psychotic experiences that are most associated with risk for clinical disorder, the specificity of risk associated with psychotic experiences, and the possible adaptive advantages of these experiences.