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Attempts to identify people at imminent risk of psychotic disorder have been made during the past 20 years. High-risk criteria have been developed, and despite findings of a recent decline in the rate of onset of psychosis associated with these criteria, people identified still have a significantly greater risk, compared with the general population. Intervention studies in this group indicate that psychological treatments and fish oil appear to be just as effective as antipsychotics. Future research should refine risk factors for psychosis and examine outcomes other than psychosis. Research is also needed into what harms and benefits are associated with making the high-risk criteria into a formal diagnosis. [ABSTRACT FROM AUTHOR]

Over the last fifteen years attempts have been made to prospectively identify individuals in the prodromal phase of schizophrenia and other psychotic disorders. The 'ultra high risk' approach, based on a combination of known trait and state risk factors, has been the main strategy used. The validation of the ultra high risk criteria led to a series of intervention studies in this population. The aim of this paper is to provide an overview of ultra high risk research. We review studies in this area, focusing on intervention research. Intervention studies have included the use of low dose antipsychotic medication, cognitive therapy, and omega-3 fatty acids. The evidence for specific intervention strategies for this population is moderate and requires replication with larger samples. Recently, it has been proposed to include an adaption of the ultra high risk criteria in the next version of the Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition). This has raised some controversy in the field. The authors conclude that it would be premature to include the Risk Syndrome in the Diagnostic and Statistical Manual of Mental Disorders at this stage. [ABSTRACT FROM AUTHOR]

Abstract: “Transition to psychosis” has been the outcome of interest in Ultra High Risk (UHR) and “prodromal” studies. However, the point at which an individual crosses the line from high risk or prodromal state to psychosis threshold is arbitrary. There have been few attempts to examine whether this threshold has any validity in terms of biological markers or course and outcome. More research is needed to determine if the current point at which a person is declared “psychotic” is valid. Indeed some persons labeled as having developed psychosis may quickly recover. In such a situation their transition could be seen as “trivial”. Others who do not make “transition” may have worse outcomes. Validation of the transition point is an important issue as “risk syndrome for psychosis” (psychosis prodrome) is being considered for inclusion in the DSMV. Further, much research attempts to distinguish markers for psychotic disorders by examining the differences between UHR individuals who do and do not develop psychosis. Thus it behooves us not just to have this risk syndrome validated, but to have the hypothetical endpoint of psychosis validated as well. [Copyright &y& Elsevier]

Abstract: The proposed Risk Syndrome for Psychosis (RS) criteria are derived from the Ultra High Risk criteria (UHR) and prodromal or Clinical High Risk criteria (CHR), and consist of subthreshold or attenuated positive psychotic symptoms with operationalized recency and frequency criteria. The rationale behind the proposed inclusion of the RS in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSMV) is that several studies have found that the UHR/prodromal/CHR criteria predict onset of psychotic disorder, mainly schizophrenia, within a brief time period of a few years. Identifying individuals meeting these criteria thus affords the possibility of early intervention to prevent or delay onset of full blown psychotic disorder. However, the RS is yet to be properly validated. Additionally, there are potential dangerous unintended consequences of the reification of this syndrome as a formal diagnosis. Thus we feel it is premature to justify inclusion of the RS in the DSM. [Copyright &y& Elsevier]

There is a higher incidence of psychotic disorders in more socially deprived neighbourhoods and a higher risk in migrants living in neighbourhoods of low ethnic density. Yet it is unclear at what stage these neighbourhood environmental factors exert an influence on the risk for psychosis. 166 Ultra high risk for psychosis young people were included in this study. Neighbourhood data were obtained from the Australian Bureau of Statistics. There was a trend for UHR individuals to reside in relatively more deprived areas and there was no association between the rate of identification of UHR migrants and neighbourhood ethnic density. [ABSTRACT FROM AUTHOR]

Abstract: Background: Identification of individuals “prodromal” for schizophrenia and other psychotic disorders relies on criteria that predict onset within a brief period. Previous trials and biological research have been predicated on the view that certain “ultra high risk” (UHR) criteria detect “the prodrome”, but there is a need to test the validity of these criteria. Aim: To assess the predictive validity of the UHR criteria in a clinical population. Method: The presence of UHR criteria was determined in 292 help-seeking individuals. At 2 year follow-up the number of new cases of psychotic disorder was assessed. Results: The criteria significantly predicted onset of psychotic disorder within 2 years. The transition rate of 16% was much lower than in initial cohorts (over 40%). Conclusions: The predictive validity of UHR criteria depends on the sample to which they are applied. Although young help-seekers meeting these criteria are at greater risk of psychotic disorder than those who do not meet them, caution is needed in their management, since a high transition rate can no longer be assumed. [Copyright &y& Elsevier]

Background: No biological treatment has been firmly established for the at‐risk stage of psychotic disorder. In this study we aim to test if subthreshold psychotic symptoms can be effectively treated with cannabidiol (CBD), a non‐psychoactive compound of the plant Cannabis sativa. The question has taken on increased importance in the wake of evidence questioning both the need and efficacy of specific pharmacological interventions in the ultra‐high risk (UHR) for psychosis group. Methods: Three‐arm randomized controlled trial of 405 patients (135 per arm) aged 12–25 years who meet UHR for psychosis criteria. The study includes a 6‐week lead‐in phase during which 10% of UHR individuals are expected to experience symptom remission. Participants will receive CBD (per oral) at doses 600 or 1000 mg per day (fixed schedule) for 12 weeks. Participants in the third arm of the trial will receive matching placebo capsules. Primary outcome is severity of positive psychotic symptoms as measured by the Comprehensive Assessment of At‐Risk Mental States at 12 weeks. We hypothesize that CBD will be significantly more effective than placebo in improving positive psychotic symptoms in UHR patients. All participants will also be followed up 6 months post baseline to evaluate if treatment effects are sustained. Conclusion: This paper reports on the rationale and protocol of the Cannabidiol for At Risk for psychosis Youth (CanARY) study. This study will test CBD for the first time in the UHR phase of psychotic disorder. [ABSTRACT FROM AUTHOR]

Abstract: Morphologic abnormalities of the insular cortex have been described in psychotic disorders such as schizophrenia, but it remains unclear whether these changes predate the onset of psychosis or develop progressively over the course of illness. In this study, we used magnetic resonance imaging to investigate the gray matter volume of the long and short insular cortices in 97 neuroleptic-naïve individuals at ultra-high-risk (UHR) for developing psychosis [of whom 31 (32%) later developed psychosis (UHR-P) and 66 (68%) did not (UHR-NP)] and 55 age- and gender-matched healthy comparisons. We also conducted a longitudinal comparison of the insular cortex gray matter changes in 31 UHR individuals (20 UHR-NP and 11 UHR-P) and 20 controls for whom follow-up MRI data between 1 and 4 years later were available. In the cross-sectional comparison, the UHR-P subjects had a significantly smaller insular cortex compared with the UHR-NP subjects bilaterally and with the controls on the right hemisphere, especially for the short insular region. More severe negative symptoms in UHR-P subjects at baseline were associated with smaller volumes of the right long insular cortex. In the longitudinal comparison, the UHR-P subjects showed greater gray matter reduction of insular cortex bilaterally (−5.0%/year) compared with controls (−0.4%/year) or UHR-NP subjects (−0.6%/year). Our findings suggest that insular cortex gray matter abnormalities in psychotic disorders may reflect pre-existing vulnerability, but that there are also active progressive changes of the insular cortex during the transition period into psychosis. Whether these longitudinal changes are features of the disorder or related to treatment with antipsychotic medication remains to be determined. [Copyright &y& Elsevier]

Abstract: Abnormal neurodevelopment in midline structures such as the adhesio interthalamica (AI) has been reported in psychotic disorders, but it is unknown whether individuals at risk for the disorder share the AI findings observed in patients with florid psychosis. Magnetic resonance imaging of 162 patients with first-episode psychosis (FEP), 89 patients with chronic schizophrenia, 135 individuals at ultra high-risk (UHR) of psychosis (of whom 39 later developed psychosis), and 87 healthy controls were used to investigate the length and prevalence of the AI. The relation of the AI length to lateral ventricular enlargement was also explored. The patients with FEP and chronic schizophrenia as well as UHR individuals had a shorter AI than the controls, but there was no difference in the AI findings between the UHR individuals who did and did not subsequently develop psychosis. There was a negative correlation between the AI length and lateral ventricular volume in all the diagnostic groups. The absence of the AI was more common in the chronic schizophrenia patients when compared with all other groups. These results support the notion that the AI absence or shorter length could be a neurodevelopmental marker related to vulnerability to psychopathology, but also suggest that schizophrenia patients may manifest progressive brain changes related to ongoing atrophy of the AI after the onset. [Copyright &y& Elsevier]

Background: The association between cannabis use and the development of a first psychotic episode was studied in a group of 100 young people identified as being at very high risk for the onset of psychosis. Method: The ‘ultra’ high risk cohort was identified by the presence of subthreshold psychotic symptoms, or a combination of first-degree relative with a psychotic disorder and recent functional decline. Thirty-two per cent of the cohort developed an acute psychotic episode over the 12-month period after recruitment. As a component of a larger research study, the level of cannabis use by participants in the year prior to enrolment in the study was assessed at intake. Results: Cannabis use or dependence in the year prior to recruitment to this study was not associated with a heightened risk of developing psychosis over the following 12-month period and therefore did not appear to contribute to the onset of a psychotic disorder. Conclusion: The results of this study suggest that cannabis use may not play an integral role in the development of psychosis in a high-risk group. While this study does not support a role for cannabis in the development of first-episode psychosis, we cannot conclude that cannabis use should be completely ignored as a candidate risk factor for onset of psychosis. A number of weaknesses of the study (the low level of cannabis use in the current sample, the lack of monitoring of cannabis use after intake) suggest that it may be premature to dismiss cannabis use as a risk factor for the development of psychosis and further research is urged in this area. [ABSTRACT FROM AUTHOR]

Emerging evidence suggests young people at ultra-high risk for psychosis (UHR) are also at-risk for poor physical health, and display high rates of modifiable cardiometabolic risk factors. However, before we can develop effective interventions there is a need to understand factors affecting lifestyle choices in the UHR group. We conducted semi-structured qualitative interviews with 20 UHR individuals (50% male; mean age 21.7), 5 parents (4 mothers, 1 father), and 6 clinicians from early intervention services in the Northwest of England to identify barriers and facilitators to living a healthy lifestyle, including achieving regular exercise, eating well and refraining from excessive substance use. Thematic analysis revealed the main barriers to living a healthy lifestyle related to psychiatric symptoms, beliefs about self, social withdrawal and practical considerations such as accessibility and cost. Provision of social support and promoting autonomy emerged as the two main themes which would facilitate a healthy lifestyle. Promoting physical health in people with emerging symptoms of psychosis is an important, yet neglected area of mental health practice and warrants further investigation. UHR individuals experience numerous barriers to living a healthy lifestyle, and interventions should focus primarily on targeting autonomous motivation and providing social support to facilitate this change. [ABSTRACT FROM AUTHOR]

Aim On the basis of applying 'ultra-high-risk' ( UHR) criteria, initially high rates of transition to psychosis were reported. However, a decline in transition to psychosis has been observed in recent years. The current descriptive paper aims to investigate if this drop in transition rate may be due to potential changes in patterns of referral to a large UHR clinic. Methods One hundred fifty young people who were referred to the Personal Assessment and Crisis Evaluation ( PACE) Clinic in Melbourne, Australia, between August 2000 and July 2004 were included. Their referral pathways were assessed using a semistructured interview. Results were compared with a similar study of a cohort referred to the same clinic between 1995 and 1996. Results The mean number of contacts prior to referral to the PACE Clinic was 1.93 (standard deviation ( SD) = 1.15), and the average time between symptom onset and referral to PACE was 46.5 weeks ( SD = 57.4). In comparison with the earlier cohort (mean = 2.36; SD = 1.32), our results indicate a lower number of contacts ( Cohen's d = 0.35, r = 0.17). Furthermore, participants in the current study were referred twice as fast to the PACE Clinic. Conclusions Increasing awareness of UHR symptoms among professionals and in the general population seems to have resulted in faster referral of young people to specialized mental health services. The global drop in transition rate might be due to a change in referral pathways to UHR services. [ABSTRACT FROM AUTHOR]

Objective Despite social environmental factors such as deprivation, urbanicity, migration and adversity being established risk factors for psychotic disorders, there is a paucity of knowledge on the influence of social environmental risk factors in the UHR population. Firstly, we aimed to investigate the association between social deprivation and risk of transition and secondly, we aimed to investigate the association between migration status and the risk of transition. Method UHR individuals at the Personal Assessment and Crisis Evaluation (PACE) service in Melbourne were included. Social deprivation as assessed according to postal code area of residence was obtained from census data and Cox regression analysis was used to calculate hazard ratios. Results A total of 219 UHR individuals were included and over the median follow-up time of 4.8 years, 32 individuals (14.6%) were known to have transitioned to a psychotic disorder. 8.8% of UHR individuals were first generation migrants and 41.9% were second generation migrants. The level of social deprivation was not associated with the risk of transition (p = 0.83). Similarly, first or second generation migrants did not have an increased risk of transition to psychosis (p = 0.84). Conclusions Despite being established risk factors for psychotic disorders, social deprivation and migrant status have not been found to increase the risk of transition in a UHR population. [ABSTRACT FROM AUTHOR]

Abstract: Three types of orbitofrontal cortex (OFC) sulcogyral patterns have been identified in the general population. The distribution of these three types has been found to be altered in individuals at genetic risk of psychosis, and in patients with first episode psychosis (FEP) and chronic schizophrenia. This study aims at establishing whether altered OFC sulcogyral patterns were present in a large cohort of individuals at ultra high risk (UHR) for psychosis. OFC pattern type was classified and the number of posterior and intermediate sulci present on the surface of the OFC was counted. OFC sulcogyral type and the number of sulci were compared between controls (n=58) and UHR participants who transitioned (n=49) versus those who did not transition (n=77) to psychosis. Finally, the relationship between sulcogyral type and number of sulci with intellectual quotient (IQ), symptom severity and social functioning of UHR individuals was explored. In line with other studies conducted in chronic schizophrenia and FEP, UHR individuals who later transitioned to psychosis showed a reduced incidence of the Type I OFC on the right hemisphere compared to controls (χ2 =19.847, p<0.001). These highly consistent results point towards the protective effect of possessing a Type I OFC in the right hemisphere. Furthermore, OFC sulcus counts revealed that controls presented with a higher number of posterior (right hemisphere; χ2 =11.658, p=0.003) and intermediate sulci (left: χ2 =6.643, p=0.036; right: χ2 =11.726, p=0.020) when compared to UHR individuals. However, no associations between OFC types or sulcus count and IQ, symptoms and functioning were observed. [Copyright &y& Elsevier]

Abstract: Few studies have addressed the correlates of trauma in young people at Ultra-High Risk (UHR) of developing a psychotic disorder. We aimed to examine baseline differences in intensity, form and content of attenuated positive psychotic symptoms, other clinical symptomatology and comorbidity between UHR patients with and without a history of trauma. In a sample of 127 UHR individuals (53 male, 74 female; mean age 18.2 years, range 14–26) we assessed trauma history and baseline symptomatology using an audit tool developed to retrieve data from patient medical records. 56% of the subjects had experienced at least one type of trauma. The intensity of perceptual abnormalities was significantly higher in the group with a history of physical abuse and ‘other trauma’ compared to those without a trauma history. Physical abuse was related to higher levels of visual disturbances, suspiciousness, grandiose beliefs and low mood compared to those without a history of physical abuse. Sexual trauma was related to perceptual disturbances with abusive content and PTSD symptoms. The prevalence of previous trauma in people at UHR of developing psychosis is high. Our findings tentatively suggest that different types of trauma may impact differently on initial presentation to UHR services. [Copyright &y& Elsevier]

Aim Research in the phenomenological tradition suggests that the schizophrenia spectrum is characterized by disturbance of the 'basic' self, whereas borderline personality disorder involves disturbance of the 'narrative' self. The current study investigated this proposal in an ultra-high risk for psychosis sample. Methods The sample consisted of 42 ultra-high-risk participants with a mean age of 19.22 years. Basic self-disturbance was measured using the Examination of Anomalous Self- Experience. Borderline personality pathology was measured using the borderline personality disorder items from the Structured Clinical Interview for DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition) Axis II Personality Questionnaire. Results No correlation was found between the measures of basic self-disturbance and borderline personality pathology. Conclusions The finding is consistent with the proposal that different (although not mutually exclusive) types of self-disturbance characterize the schizophrenia spectrum and borderline personality disorder. Further research should further examine the question of basic self-disturbance in patients with established borderline personality disorder. [ABSTRACT FROM AUTHOR]

Abstract: Background: Baseline functioning has been found to be a strong predictor of transition to psychosis in ultra high risk populations. However, the time course of functioning may enhance prediction. We investigated whether there were different patterns of functioning over time and whether particular temporal patterns were related to baseline characteristics and psychosis outcome. Method: Functional data was assessed at baseline and after 3 to 6year follow-up in an ultra high risk sample (n=158; 92 female, mean age=19.28 (SD=3.33), range=14–29). Using the median score of the GAF and the QLS scale, a ‘High’ and ‘Low’ group (comprising of subjects functioning above or below median at both baseline and follow-up) and a ‘Deterioration’ group and ‘Improving’ group were created. Results: Chi-square analyses showed that the Low and Deteriorating functioning groups were the most likely to develop first-episode psychosis (FEP). Importantly, UHR individuals with deteriorating functioning were at higher risk of transition than those whose functioning was low at baseline but improved over time (GAF: X 2 =5.10, df=1, p=.02; QLS: X 2 =9.13, df=1, p=.003). Binary logistic regression analyses showed that a decline in functioning was more strongly associated with FEP (GAF: p=<.0001; QLS: p<.0001) than the level of baseline functioning (GAF: p=.005; QLS: p=.09). The deteriorating group could not be distinguished from the High group in terms of baseline symptomatology. Discussion: With the addition of the ‘low functioning’ criterion to the UHR criteria, we may miss out on some true positive cases. Limiting our attention to baseline poor functioning may therefore distort the picture in terms of risk for psychosis. [Copyright &y& Elsevier]

Abstract: Reports suggesting that schizophrenia participants are more likely to be phenylthiocarbamide (PTC) non-tasters when compared to controls have recently been controversial. If supported, a genetic-based phenotypic variation in PTC taster status is implicated, suggesting a greater illness risk for those participants with recessive alleles for the TAS2R38 receptor. Should PTC insensitivity be a schizophrenia endophenotype, then it would be expected in follow-up of ultra high-risk for psychosis participants who later develop schizophrenia (UHR-S). UHR-S was hypothesised to show reduced PTC sensitivity compared to those who were previously at risk, but did not transition (UHR-NP). PTC perception was assessed in 219 UHR participants at long-term follow-up, of whom 53 had transitioned to psychosis (UHR-P) during the follow-up period. Fifteen of the 219 participants were diagnosed with schizophrenia. Seventy-eight had a family history of psychotic disorder. No differences in PTC taster status were found in UHR participants based upon transition to psychosis status, schizophrenia diagnosis, or family history of schizophrenia. This report indicates that schizophrenia development among UHR participants is not associated with PTC tasting deficits and fails to support previous findings that inability to detect the bitter taste of PTC is a schizophrenia endophenotype. [Copyright &y& Elsevier]

Abstract: Although the hippocampus is a key brain region in the pathophysiology of schizophrenia, it is unclear whether structural or biochemical abnormalities predate illness onset. In this study, we used magnetic resonance imaging and spectroscopy data acquired prior to both the onset of psychosis and treatment with antipsychotics to determine this. Sixty-six young people clinically at ultra high-risk of development of psychosis were recruited, 59 of whom did not later develop a psychotic disorder and 7 who had done so after at least 24months follow-up. These participants were compared with 29 healthy comparison subjects on multiple independent magnetic resonance measures: hippocampal volume, hippocampal T2 relaxation time, and medial temporal lobe metabolite concentrations (including N-acetylaspartate). We found similar reductions in left hippocampal volume in the at-risk group compared to comparison subjects regardless of later transition status; on the right this only reached significance for the at-risk group who did not transition to psychosis. T2 relaxation time in the left hippocampal head was significantly elevated in the later-psychotic group, and this elevation positively correlated with total positive symptoms in the UHR group as a whole. Medial temporal lobe metabolite concentrations did not differ. These findings suggest that there are subtle pathological changes in the hippocampus prior to the development of psychosis, but that they are limited to the left hippocampal head. However, standard measures of neuroanatomical disturbance do not appear to be predictive of later transition, and instead are likely to be non-specific and common in cases that later develop a non-psychotic disorder. [Copyright &y& Elsevier]

Abstract: Individuals at “ultra high risk” (UHR) for psychosis have been found to experience high rates of sexual trauma. An aetiological role for sexual trauma has been proposed for psychotic disorders and may influence psychotic symptom content. We aimed to investigate the relationship between previous sexual trauma and reported psychotic-like experiences, in particular psychotic symptoms with a sexual content in a UHR sample. We investigated the prevalence of “attenuated” or “subthreshold” psychotic symptoms with a sexual content in a consecutive series of patients recruited to a specialist UHR clinic. Patient''s experience of general and sexual trauma was rated separately using a trauma questionnaire based on the list of events qualifying as traumas under DSM IV. The sample consisted of 92 patients, 14 (15.2%) had experienced an attenuated psychotic symptom with sexual content. The most common symptom was overvalued ideas/delusions of being watched in the shower/toilet or undressing. A considerable proportion of the sample (36.2%) had experienced sexual trauma (sexually molested or raped). Presence of attenuated psychotic symptoms with sexual content was related to history of previous sexual trauma (OR 7.17, P <0.01). This relationship remained significant when other traumatic experiences, PTSD diagnosis, age and sex were adjusted for. Further research into this relationship with regard to outcome and treatment is warranted. [Copyright &y& Elsevier]