Ultra-high Risk Cohort Research Articles

Cognitive functioning in ultra-high risk for psychosis individuals with and without depression: Secondary analysis of findings from the NEURAPRO randomized clinical trial

Neurocognitive impairments are well established in both ultra-high risk (UHR) for psychosis and major depressive disorder (MDD). Despite this understanding, investigation of neurocognitive deficits in UHR individuals with MDD and its association with MDD within this population, has been scarce. Hence, this study aimed to examine any differences in neurocognition at baseline between those with MDD at baseline and those with no history of MDD, as well as determine whether neurocognitive variables are significantly associated with meeting criteria for MDD at follow-up, while controlling for relevant clinical variables, within a UHR cohort. Data analysis was conducted on 207 participants whose baseline neurocognition was assessed using Brief Assessment of Cognition for Schizophrenia, as part of a trial of omega-3 fatty acids (NEURAPRO) for UHR individuals. While baseline MDD was the strongest predictor, poorer verbal memory and higher verbal fluency were significantly associated with MDD at 12 months (p = .04 and 0.026, respectively). Further, higher processing speed was significantly associated with MDD at medium-term follow-up (p = .047). These findings outline that neurocognitive skills were independently associated with meeting criteria for MDD at follow-up within UHR individuals, with novel findings of better verbal fluency and processing speed being linked to MDD outcomes. Hence, neurocognitive performance should be considered as a marker of risk for MDD outcomes and a target for management of MDD in UHR.

Frontal slow wave resting EEG power is higher in individuals at Ultra High Risk for psychosis than in healthy controls but is not associated with negative symptoms or functioning

Decreased brain activity in the frontal region, as indicated by increased slow wave EEG power measured by electrodes place on the skull over this area, in association with negative symptoms has previously been shown to distinguish ultra-high risk (UHR) individuals who later transitioned to psychosis (UHR-P) from those who did not transition (UHR-NP). The aims of the current study were to: 1) replicate these results and 2) investigate whether similar association between increased frontal slow wave activity and functioning shows any value in the prediction of transition to psychosis in UHR individuals. The brain activity, recorded using EEG, of 44 UHR individuals and 38 healthy controls was included in the analyses. Symptom severity was assessed in UHR participants and functioning was measured in both groups. The power in the theta frequency band in the frontal region of UHR individuals was higher than in controls. However, there was no difference between the UHR-P and the UHR-NP groups, and no change in slow frequency power following transition to psychosis. The correlation between delta frequency power and negative symptoms previously observed was not present in our UHR cohort, and there was no association between frontal delta or theta and functioning in either group. Increased delta power was rather correlated with depressive symptoms in the UHR group. Future research will be needed to better understand when, in the course of the illness, does the slow wave activity in the frontal area becomes impaired.

Profiling of Oncogenic Signaling in Multiple Myeloma — Association with Biology, Disease Progression and Prognosis

Introduction: The pathogenesis of multiple myeloma (MM) involves complex genetic and epigenetic alterations, which ultimately affect oncogenic signaling networks. Analysis of pathway activation in primary MM cells within their native microenvironment will not only increase our understanding of MM cell biology but may open up new avenues towards tailored therapies that target individually activated signaling cascades.Methods: We established a (phospho-) immunohistochemistry (IHC)-assay to analyze key activation markers of oncogenic pathways and networks, namely RAS/RAF/MEK/ERK, PI3K/AKT, JAK/STAT3, canonical NFκB, and cMyc, in an exploratory cohort of 459 bone marrow (BM) biopsies from patients with smoldering MM (SMM), newly diagnosed symptomatic (NDMM) and refractory MM (RRMM). An independent validation cohort comprised BM samples from 462 NDMM patients who were uniformly treated within clinical trials. To integrate activation intensity and spread scores for each pathway and sample, non-linear principal component analysis (PCA) was applied.Results: Pathway profiling in progressing stages of plasma cell disorders showed the canonical NFκB pathway as nearly universally activated in SMM (97% of patients); signals for AKT, ERK, STAT3, and cMyc were only seen in subsets of SMM patients (≤33%), with STAT3 being the least activated pathway (6%). In NDMM and RRMM, NFκB activation significantly decreased to 90% and 82% of patients, respectively (p=0.02). In contrast, we observed a significant increase in activation of all other pathways and cMyc from SMM to NDMM and further to RRMM patients (p<0.001). All of these pathways were activated in at least 50% of RRMM. Analysis of 34 patients with available longitudinal samples confirmed a significant increase in strong activation of STAT3 and cMyc with progressing disease stages.Assessment of pathway clustering and interdependencies showed a strong negative correlation between NFκB and ERK in all disease stages. In contrast, a positive correlation was seen between cMyc and STAT3 as well as between AKT and ERK activation with increasing strength over progressing disease stages. Interestingly, when focusing on strong activation signals as determined by PCA, virtual absence of simultaneous activation of more than one pathway in SMM was observed, while pathway co-activation significantly increased in NDMM and RRMM (22% and 34%, p<0.001).Activation of STAT3 and expression of cMyc were significantly associated with higher ISS stage in NDMM of both the exploratory and the validation cohort. STAT3 pathway activation was also significantly associated with gain(1q21). In the validation cohort with available gene expression profiling (GEP) data, both STAT3 (p=0.02) and cMyc (p<0.001) activation showed a significant association with high risk disease according to GEP risk scores.Assessment of the impact of pathway activation on survival in the validation cohort showed expression of cMyc (p=0.01), activation of STAT3 (p=0.005) and cMyc-STAT3 co-activation (p=0.005) to negatively influence PFS. Expression of cMyc (p=0.02) and cMyc-STAT3 co-activation (p=0.02) were also significantly associated with inferior OS. STAT3 activation showed a negative trend towards inferior OS (p=0.08). Accounting for GEP-defined risk status, STAT3 pathway activation defined an ultra-high risk cohort. Assessment of differential gene expression suggested an autocrine positive feedback loop of IL-6 signaling and an enrichment of cell cycle associated genes in patients with STAT3 activation.Conclusions: Activation of either NFkB or ERK/AKT signaling appears to be a hallmark of MM. Later stages of MM are characterized by activation of additional signaling pathways that may affect therapy response. Importantly, cMyc expression and JAK/STAT3 pathway activation show adverse prognostic impact and significantly increase with disease progression. DisclosuresGoldschmidt:Sanofi: Consultancy, Research Funding; Adaptive Biotechnology: Consultancy; Amgen: Consultancy, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; ArtTempi: Honoraria; Novartis: Honoraria, Research Funding; Mundipharma: Research Funding; Chugai: Honoraria, Research Funding; Takeda: Consultancy, Research Funding. Raab:BMS: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria.

Early intervention for everyone? A review of cross-cultural issues and their treatment in ultra-high-risk (UHR) cohorts

Over the past 20 years, early management of psychosis has become both a research and policy priority. In Western countries, psychotic disorders appear more prevalent in migrant and minority ethnic groups than in native or dominant groups. Moreover, disparities exist in health conditions and access to care among immigrants and minority ethnic groups, compared with native-born and majority groups. Appropriate early detection tools are necessary for the different groups. This systematic review provides a synthesis of the assessment and discussion of transcultural issues in ultra-high-risk (UHR) cohorts. The Medline database was searched via PubMed for peer-reviewed articles published in English from 1995 to 2017. All 79 studies included are prospective UHR cohort studies that used the Comprehensive Assessment of At-Risk Mental States (CAARMS). In UHR cohort studies that used the CAARMS, transcultural data (native language, ethnicity, place of birth, migration) are rarely collected, and inadequate ability to speak the dominant language is a common exclusion criterion. When they are included, the CAARMS scores differ between some minorities and the native-born majority group. This systematic review demonstrates barriers to the access to participation in early intervention research for migrants and ethnic minorities. This selection bias may result in lower validity for the CAARMS among these populations and thus in inadequate intervention programmes. Along with targeted studies, minorities' access to participation in UHR cohorts should be improved through 3 tools: interpreters at recruitment and for administration of CAARMS, a guide to cultural formulation and transcultural data collection.

Clinical trajectories in the ultra-high risk for psychosis population

BackgroundTraditionally, research in the ultra-high risk (UHR) for psychosis population has focused on the treatment of existing symptomatology and prevention of transition to psychosis. Recently, there has been an increase in focus on outcomes in individuals who do not transition to psychosis. However, there is a lack of standardised definitions of remission, recovery, recurrence and relapse in UHR, resulting in the inability to generalise and replicate outcomes. MethodThe aims of the current study were to develop definitions for remission, recovery, recurrence and relapse, and apply them to a UHR cohort allowing the identification of longitudinal clinical trajectories. Further stratification in broader categories of favourable and unfavourable outcomes was applied. The predictive value of various baseline factors on specific clinical trajectories was also assessed. Results17 different trajectories were identified in a cohort of 202 individuals within a 12-month period and classified according to the suggested definitions for recovery (35.7%), remission (7.5%), any recurrence (20%), no remission (17.3%), relapse (4.0%) and transition to psychosis (15.8%). Favourable and unfavourable trajectories represented 43.2% and 57.1% respectively. Long duration of untreated symptoms and high depression scores were associated with unfavourable outcomes. DiscussionIt is possible to apply clear definitions of remission, recovery, recurrence, relapse and transition to psychosis to a UHR cohort to evaluate longitudinal clinical trajectories. Acceptance and use of these definitions will help to facilitate comparisons between trials and to improve clinical clarity across the range of available therapeutic options in UHR individuals.

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.

Impaired mismatch negativity to frequency deviants in individuals at ultra-high risk for psychosis, and preliminary evidence for further impairment with transition to psychosis

BackgroundThere is evidence to suggest that people with established psychotic disorders show impairments in the mismatch negativity induced by a frequency-deviant sound (fMMN), and that these impairments worsen with the deterioration of psychotic symptoms. This study aimed to test whether individuals at ultra-high risk (UHR) for psychosis show pre-morbid impairments in fMMN, and if so, whether fMMN continues to deteriorate with transition to psychosis. MethodfMMN was recorded in a cohort of UHR individuals (n=42) and compared to healthy controls (n=29). Of the 27 UHR participants who returned for a second EEG session, six participants had transitioned to psychosis by 12-month follow-up (UHR-T) and were compared to the 21 participants who did not transition (UHR-NT). ResultsfMMN amplitude was significantly reduced, relative to healthy controls, in the UHR cohort. Furthermore, UHR-T individuals showed a significant decrease in fMMN amplitude over the period from baseline to post-transition; this reduction was not observed in UHR-NT. ConclusionsThese results suggest that fMMN is abnormal in UHR individuals, as has repeatedly been found previously in people with established psychotic disorders. The finding that fMMN impairment worsens with transition to psychosis is consistent with the staging model of psychosis; however, caution must be taken in interpreting these findings, given the extremely small sample size of the UHR-T group.

Long-term employment among people at ultra-high risk for psychosis

BackgroundPsychotic disorders are associated with high rates of sustained unemployment, however, little is known about the long-term employment outcome of people at ultra-high risk (UHR) of developing psychosis. We sought to investigate the long-term unemployment rate and baseline predictors of employment status at follow-up in a large UHR cohort. Method268 UHR patients recruited from the Personal Assessment and Crisis Evaluation clinic in Melbourne, Australia were followed-up over 2–14years after initial presentation to the service. Individuals in no form of employment or education were classed as unemployed. Logistic regression analyses were used to examine predictors of employment outcome. ResultsA high rate of unemployment was present at follow-up in this UHR sample (23%). At baseline, those who were unemployed at follow-up had a longer duration of untreated illness, more severe negative symptoms, lower IQ, poorer social and occupational functioning and reported more childhood trauma than the employed group. At follow-up, unemployed individuals exhibited significantly more severe symptoms on all measures and were more likely to have been diagnosed with a mood, anxiety, psychotic or substance use disorder. Childhood trauma and the duration of untreated illness at baseline were significant independent predictors of employment status at follow-up in the multivariate analyses. ConclusionsNearly a quarter of this UHR sample was unemployed at long-term follow-up. The duration of untreated illness and the effects of childhood trauma are potentially modifiable risk factors for long-term employment outcome in this group. Vocational support may be beneficial for many UHR patients presenting to services.

Do affective or dissociative symptoms mediate the association between childhood sexual trauma and transition to psychosis in an ultra-high risk cohort?

We have previously reported an association between childhood sexual trauma and transition to psychosis in an Ultra High Risk (UHR) population. We aimed to investigate if this association was mediated by affective or dissociative symptoms. Data were from a large UHR for psychosis cohort study. None of the potential mediators (depression, anxiety, dissociation, mood swings and mania, assessed by the HAM-D, HAM-A and the CAARMS symptom scales) significantly mediated the total association between sexual abuse scores and transition. At the point of transition, the mechanistic pathway from sexual trauma to psychosis does not appear to operate through affective symptoms.

Presynaptic Striatal Dopamine Dysfunction in People at Ultra-high Risk for Psychosis: Findings in a Second Cohort

Using positron emission tomography (PET), we previously observed increases in 3,4-dihydroxy-6-[(18)F]fluoro-L-phenylalanine ((18)F-DOPA) uptake in the striatum of subjects at ultra-high risk (UHR) for psychosis, indicating elevated presynaptic dopamine synthesis capacity. The purpose of this study was to test if this finding would be replicated in a second UHR cohort. (18)F-DOPA PET was used to estimate dopamine synthesis capacity in the striatum of an entirely new cohort of 26 individuals at UHR for psychosis (14 males, mean±SD age = 22.7±4.7 years) and 20 healthy volunteers matched for age and gender (11 males, mean±SD age = 24.5±4.5 years). Dopamine synthesis capacity was elevated in the whole [t(44) = 2.6; p = .01, effect size = .81] and associative striatum [t(44) = 2.6; p = .01, effect size = .73] of UHR compared with control subjects. When the two samples were combined to give a final sample of 32 control and 50 UHR subjects, the higher levels of dopamine synthesis capacity in the UHR group reached significance across the whole [F(1,81) = 11.0; p = .001], associative [F(1,81) = 12.7; p = .001], and sensorimotor [F(1,81) = 4.7; p = .03], but not the limbic [F(1,81) = 2.1; p = .2], striatum. The findings indicate that elevated dopamine synthesis capacity in the dorsal striatum is a robust feature of individuals at UHR for psychosis and provide further evidence that dopaminergic abnormalities precede the onset of psychosis.

Update on Omega-3 Polyunsaturated Fatty Acids in Early-Stage Psychotic Disorders

Polyunsaturated fatty acids (PUFAs) are the major constituents of cell membrane phospholipids. As such, they have multiple important biological roles, including in receptor binding, neurotransmission, signal transduction, and eicosanoid synthesis. A growing body of studies suggests significant reductions in PUFA levels in people with schizophrenia (Berger et al, 2006). Concordant with these findings, fatty acids, particularly the omega-3 PUFA, may have a beneficial role in the treatment of first-episode schizophrenia, and in the prevention of schizophrenia, while results in chronic schizophrenia have been mixed (Peet, 2008). We have recently tested whether supplementation with omega-3 PUFA could reduce the rate of transition to first-episode psychosis in an ultra-high risk (UHR) cohort. In our study, we randomized 81 individuals aged 13–25 years to 12 weeks of either 1.2 g/day of omega-3 PUFA or placebo, followed by a 40-week monitoring period. In all, 2 of 41 (4.9%) of those receiving the active agent transitioned to psychosis, compared with 11 of 40 (27.5%) in the placebo group, a statistically significant difference (Amminger et al, 2010). While PUFAs have been investigated in schizophrenia, their role in the onset of psychotic symptoms is unclear. Therefore, we examined the relationship between omega-3 PUFA (ie, alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), and docosahexaenoic acid (DHA)) levels in erythrocyte membrane phosphatidylethanolamine and measures of psychopathology in our UHR cohort at baseline. Erythrocyte membrane phospholipid composition closely reflects that of neuronal membranes, and provides an easily accessible indicator of brain phospholipids. While ALA, EPA, and DHA did not correlate significantly with any symptom measure, low levels of DPA and the summary score of all assessed omega-3 fatty acids (ie, ALA, EPA, DPA, and DHA) correlated with more severe negative symptoms. These correlations remained significant after adjustment for potential confounders (ie, age, sex, and nicotine use). Reduced DPA has been previously reported in neuroleptic-naive first-episode schizophrenia patients (Reddy et al, 2004). Given our intervention study provided support for the ‘dose–response' criterion (McNamara, 2011), as an increase in erythrocyte omega-3 PUFA levels reduced the rate of transition to psychosis and correlated with functional improvement, we tested if the subjects with the lowest erythrocyte omega-3 levels at baseline were at higher risk for transitioning to psychosis. To eliminate treatment effects, we only investigated those participants who had received placebo. Cox regression analyses with adjustment for age, sex, and nicotine use indicated that no single omega-3 PUFA or their summary score predicted conversion to psychosis. Following studies reporting lower levels of arachidonic acid (AA) and nervonic acid (NA), as well as DHA, in people with schizophrenia (Assies et al, 2001), we also examined if these fatty acids predicted transition to psychosis. While AA was not found to be predictive, low NA levels at baseline significantly predicted transition to psychosis (Amminger et al, submitted). As NA is a major constituent of the myelin sheath, low levels of NA could reflect suboptimal myelination in those UHR individuals who develop a psychotic disorder. The finding is consistent with the well-established finding of white matter abnormalities in schizophrenia (Ellison-Wright and Bullmore, 2009). Notably, the observation that supplementation with omega-3 PUFAs may prevent transition to psychosis suggests that omega-3 fatty acids may offset the risk conferred by decreased levels of NA. A randomized controlled multicenter phase III clinical trial of omega-3 PUFA is now underway to replicate the findings (Australian New Zealand Clinical Trials Registry - ACTRN12608000475347).

Comparison of Experiences of Stress and Coping Between Young People at Risk of Psychosis and a Non-Clinical Cohort

Although the experience of stress and associated coping responses are thought to play a role in the onset of schizophrenia and other psychotic disorders, there is little empirical evidence to support such a relationship. The relatively recent development of validated and reliable criteria for identifying young people at "ultra" high-risk (UHR) of psychosis has enabled the process of illness onset to be studied more closely than was previously possible. This longitudinal study compared the experiences of stress and coping between a UHR cohort (N=143) and a healthy comparison group (HC group, N=32). The UHR group experienced significantly fewer life events over a 12-month period than the HC group, but there was no difference in the experience of minor events or "hassles". However, the UHR group reported feeling significantly more distressed by events, felt they coped more poorly and utilized different coping strategies. The appraisals made about stressors differentiated the groups and was associated with differences in coping and distress levels. This suggests that treatment strategies focusing on stress management and enhancing coping skills might be important components of preventive interventions.

Randomized Controlled Trial of Interventions for Young People at Ultra-High Risk of Psychosis: Study Design and Baseline Characteristics

Intervention during the pre-psychotic period of illness holds the potential of delaying or even preventing the onset of a full-threshold disorder, or at least of reducing the impact of such a disorder if it does develop. The first step in realizing this aim was achieved more than 10 years ago with the development and validation of criteria for the identification of young people at ultra-high risk (UHR) of psychosis. Results of three clinical trials have been published that provide mixed support for the effectiveness of psychological and pharmacological interventions in preventing the onset of psychotic disorder. The present paper describes a fourth study that has now been undertaken in which young people who met UHR criteria were randomized to one of three treatment groups: cognitive therapy plus risperidone (CogTher + Risp: n = 43); cognitive therapy plus placebo (CogTher + Placebo: n = 44); and supportive counselling + placebo (Supp + Placebo; n = 28). A fourth group of young people who did not agree to randomization were also followed up (monitoring: n = 78). Baseline characteristics of participants are provided. The present study improves on the previous studies because treatment was provided for 12 months and the independent contributions of psychological and pharmacological treatments in preventing transition to psychosis in the UHR cohort and on levels of psychopathology and functioning can be directly compared. Issues associated with recruitment and randomization are discussed.

Medium term follow-up of a randomized controlled trial of interventions for young people at ultra high risk of psychosis

Valid criteria to identify young people who are believed to be at ultra high risk (UHR) of developing a psychotic episode were developed over the last decade. The first randomized controlled trial of treatment in a UHR cohort indicated that specific pharmacotherapy and psychotherapy delayed onset of disorder, and possibly reduced incidence. This paper reports results of follow-up of that trial. 41 of the 59 (69.5%) participants in the original study agreed to follow-up. No differences were found in transition rate, level of symptomatology or functioning between participants who received a combination of psychological treatment and anti-psychotic medication compared to those who received supportive therapy alone. A significant proportion of both treatment groups reported moderate levels of psychiatric morbidity and a continuing need and desire for care at this follow-up. Low levels of hospitalisation were noted for those who did progress to psychosis. Conclusions that can be drawn from this exploratory study are limited by the relatively small number of participants in the original study and the failure to follow-up the entire cohort. Although participants may have been treated too briefly to result in enduring positive effects, there appear to have been some cost savings in inpatient mental health treatment required after the end of the trial for individuals in both treatment groups who developed psychosis.

Mapping the onset of psychosis: the Comprehensive Assessment of At-Risk Mental States

Objective: Recognizing 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.Method: Several 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.Results: High 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.Conclusions: In 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 sub threshold psychotic symptoms for worsening into full-threshold psychotic disorder.

Mapping the Onset of Psychosis: The Comprehensive Assessment of At-Risk Mental States

Recognizing 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. Several 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. High 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. In 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.

Obstetric Complications and Transition to Psychosis in an ‘Ultra’ High Risk Sample

An association between birth and pregnancy complications and the later development of schizophrenia has been described for decades and obstetric complications (OCs) have been proposed as a vulnerability marker for psychosis in line with the neurodevelopmental hypothesis of psychotic disorders. Previous studies of OCs have focused on established schizophrenia. In this study, the association between OCs and the development of psychotic disorder was studied in a group of 74 young people identified as being at very high risk for the first onset of psychosis. The "ultra" high risk (UHR) 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-eight 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 OCs experienced by the UHR cohort was assessed at intake. Obstetric complications were not associated with the later development of psychosis in the UHR group included in this study. This study does not support a role for OCs as a risk factor for the later development of psychosis; however, we cannot conclude that they should be completely ignored as a candidate risk factor for onset of psychosis. A number of weaknesses of the study suggest that it may be premature to dismiss OCs as a risk factor for the development of psychosis and further research is urged in this area.

Non-reduction in hippocampal volume is associated with higher risk of psychosis

Previous research using MRI scans has shown reduced hippocampal volumes in chronic schizophrenia and first-episode psychosis compared to well subjects. There are few MRI volumetric studies of high-risk cohorts and no studies that have compared structural measures between high-risk subjects who later developed a psychotic illness and those who did not. Therefore, the question of whether structural changes to the hippocampi precede the onset of an acute psychotic episode has not been answered. Hippocampal and whole brain volumes of 60 people at ultra high-risk (UHR) of developing a psychotic episode (identified through state and trait criteria) were obtained through MRI scan and compared with subjects with first episode psychosis (FEP: n=32), and no mental illness ( n=139). Thirty-three percent ( n=20) of the UHR cohort developed a psychotic disorder during the 12-month period following the MRI scan. The UHR group as a whole, like the FEP group, had significantly smaller left and right hippocampal volumes than the normal comparison group. Contrary to our initial hypothesis, the left hippocampal volume of the UHR subjects who developed a psychotic disorder was larger than the UHR-non-psychotic subgroup and the FEP group, but no differences were found between the UHR-psychotic and normal groups. The right hippocampus of the UHR-non-psychotic group was significantly smaller than the Normal group but not different to the FEP group. Furthermore, a larger left hippocampal volume of the UHR cohort at intake was associated with the subsequent development of acute psychosis rather than smaller volumes. These results contradicted the expected outcomes, which had been influenced by the neurodevelopmental model of the development of psychosis and an earlier study comparing hippocampal volumes of first episode, chronic schizophrenia and normal populations. One implication of these results is that a process of dynamic central nervous system change may occur during the onset phase of schizophrenia and related disorders, rather than earlier in life as suggested by the neurodevelopmental model. Alternatively, selection factors associated with the UHR cohort may have created a bias in the results. Replication of these results is required in other high-risk cohorts.