Why transition risk to psychosis is not declining at the OASIS ultra high risk service: The hidden role of stable pretest risk enrichment.

BACKGROUND: The reason for declining risk to psychosis across individuals assessed and meeting Ultra High Risk (UHR) criteria is still unclear. No studies have investigated the potential substantial role of the underlying risk enrichment across all the individuals undergoing an UHR assessment. METHODS: Cohort study including all non-psychotic subjects who were assessed on suspicion of psychosis risk by the OASIS UHR service in the period 2001 to 2015. Posttest (after UHR assessment) and pretest risk (before UHR assessment) of psychosis were stratified and compared across three time periods (2001-2005, 2006-2010, 2011-2015) with Cox analysis and modulating factors were investigated. RESULTS: The posttest risk of psychosis at the OASIS service has increased from the initial pilot years of the service (2001-2005) and then stabilised and not declined over the following decade (2006-2010 and 2011-2015). This was paralleled by a similar course of pretest risk for psychosis. Stability of pretest risk for psychosis over the past decade was associated with a lack of change in ethnicity and to counterweighting changes in the type of referral sources over different time periods. CONCLUSIONS: The time course of transition risk to psychosis in UHR services is strictly associated with the time course of pretest risk enrichment. If the latter remains stable over time, as for the OASIS service, no declining transition risk is observed over the most recent years. Pretest risk enrichment is determined by recruitment and sampling strategies. This study confirms the need to control these factors in the UHR field.

Long-term validity of the At Risk Mental State (ARMS) for predicting psychotic and non-psychotic mental disorders.

BACKGROUND: The long-term clinical validity of the At Risk Mental State (ARMS) for the prediction of non-psychotic mental disorders is unknown. METHODS: Clinical register-based cohort study including all non-psychotic individuals assessed by the Outreach And Support in South London (OASIS) service (2002-2015). The primary outcome was risk of developing any mental disorder (psychotic or non-psychotic). Analyses included Cox proportional hazard models, Kaplan-Meier survival/failure function and C statistics. RESULTS: A total of 710 subjects were included. A total of 411 subjects were at risk (ARMS+) and 299 not at risk (ARMS-). Relative to ARMS-, the ARMS+ was associated with an increased risk (HR=4.825) of developing psychotic disorders, and a reduced risk (HR=0.545) of developing non-psychotic disorders (mainly personality disorders). At 6-year, the ARMS designation retained high sensitivity (0.873) but only modest specificity (0.456) for the prediction of psychosis onset (AUC 0.68). The brief and limited intermittent psychotic symptoms (BLIPS) subgroup had a higher risk of developing psychosis, and a lower risk of developing non-psychotic disorders as compared to the attenuated psychotic symptoms (APS) subgroup (P<0.001). CONCLUSIONS: In the long-term, the ARMS specifically predicts the onset of psychotic disorders, with modest accuracy, but not of non-psychotic disorders. Individuals meeting BLIPS criteria have distinct clinical outcomes. SIGNIFICANT OUTCOMES: In the long-term, the ARMS designation is still significantly associated with an increased risk of developing psychotic disorders but its prognostic accuracy is only modest. There is no evidence that the ARMS is associated with an increased risk of developing non-psychotic mental disorders. The BLIPS subgroup at lower risk of developing non-psychotic disorders compared to the APS subgroup. LIMITATIONS: While incident diagnoses employed in this study are high in ecological validity they have not been subjected to formal validation with research-based criteria.

Towards a Standard Psychometric Diagnostic Interview for Subjects at Ultra High Risk of Psychosis: CAARMS versus SIPS.

Background. Several psychometric instruments are available for the diagnostic interview of subjects at ultra high risk (UHR) of psychosis. Their diagnostic comparability is unknown. Methods. All referrals to the OASIS (London) or CAMEO (Cambridgeshire) UHR services from May 13 to Dec 14 were interviewed for a UHR state using both the CAARMS 12/2006 and the SIPS 5.0. Percent overall agreement, kappa, the McNemar-Bowker χ (2) test, equipercentile methods, and residual analyses were used to investigate diagnostic outcomes and symptoms severity or frequency. A conversion algorithm (CONVERT) was validated in an independent UHR sample from the Seoul Youth Clinic (Seoul). Results. There was overall substantial CAARMS-versus-SIPS agreement in the identification of UHR subjects (n = 212, percent overall agreement = 86%; kappa = 0.781, 95% CI from 0.684 to 0.878; McNemar-Bowker test = 0.069), with the exception of the brief limited intermittent psychotic symptoms (BLIPS) subgroup. Equipercentile-linking table linked symptoms severity and frequency across the CAARMS and SIPS. The conversion algorithm was validated in 93 UHR subjects, showing excellent diagnostic accuracy (CAARMS to SIPS: ROC area 0.929; SIPS to CAARMS: ROC area 0.903). Conclusions. This study provides initial comparability data between CAARMS and SIPS and will inform ongoing multicentre studies and clinical guidelines for the UHR psychometric diagnostic interview.

Neurobiological Models of Self-Disorders in Early Schizophrenia.

Self-disorders (SDs) (from the German Ichstörungen) are alterations of the first-person perspective, long associated with schizophrenia, particularly in early phases. Although psychopathological features of SDs continue to be studied, their neurobiological underpinnings are unknown. This makes it difficult to integrate SDs into contemporary models of psychosis. The present review aims to address this issue, starting from an historical excursus revealing an interconnection between neuroscientific models and the origin of the psychopathological concept of SDs. Subsequently, the more recent neurobiological models related to SDs are discussed, particularly with respect to the onset of schizophrenia.

Presynaptic dopaminergic function: implications for understanding treatment response in psychosis.

All current antipsychotic drugs block dopamine (DA) receptors, but the nature of the DA dysfunction in schizophrenia has not been clear. However, consistent evidence now shows that presynaptic dopaminergic function is altered in schizophrenia, specifically in terms of increased DA synthesis capacity, baseline synaptic DA levels, and DA release. Furthermore, presynaptic dopaminergic function is already elevated in prodromal patients who later developed the disorder. Currently available antipsychotics act on postsynaptic receptors, not targeting presynaptic DA abnormalities. This has implications for understanding response and developing new treatments. The lack of normalization of the abnormal presynaptic function could explain why discontinuation is likely to lead to relapse, because the major dopaminergic function persists, meaning that once treatment stops there is nothing to oppose the dysregulated dopamine function reinstating symptoms. Furthermore, it suggests that drugs that target presynaptic dopaminergic function may constitute new treatment possibilities for schizophrenic patients, in particular, for those in whom antipsychotics are poorly effective. In addition, the longitudinal changes with the onset of psychosis indicate the potential to target a defined dynamic neurochemical abnormality to prevent the onset of psychosis.