Reduction of duration of untreated psychosis (DUP) is the key strategy of early interventions for improving the outcomes of first-episode psychosis. Although several controlled interventional studies have been conducted with the aim of reducing DUP, the results are highly inconsistent and conflicting. The current study systematically searches Web of Science and Ovid for English original articles investigating interventions adopted to reduce DUP, compared to a control intervention, up to April 6, 2017. Sixteen controlled interventional studies were retrieved, including 1964 patients in the intervention arm and 1358 in the control arm. The controlled intervention studies were characterized by standalone first episode psychosis services, standalone clinical high risk services, community interventions, healthcare professional training, and multifocus interventions. Random effects meta-analyses were conducted. There was no summary evidence that available interventions are successful in reducing DUP during the first episode of psychosis (Hedges’ g = −0.12, 95% CI = −0.25 to 0.01). Subgroup analyses showed no differences within each subgroup, with the exception of clinical high risk services (Hedges’ g = −0.386, 95% CI = −0.726 to −0.045). These negative findings may reflect a parceled research base in the area, lack of prospective randomized controlled trials (only 2 randomized cluster designed studies were present) and small sample sizes. There was substantial heterogeneity (I2 = 66.4%), most of which was accounted by different definitions of DUP onset (R2 = .88). Psychometric standardization of DUP definition, improvement of study design, and implementation of preventative strategies seem the most promising avenues for reducing DUP and improving outcomes of first-episode psychosis.

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Psychosis has been proposed to develop from dysfunction in a hippocampal-striatal-midbrain circuit, leading to aberrant salience processing. Here, we used functional magnetic resonance imaging (fMRI) during novelty salience processing to investigate this model in people at clinical high risk (CHR) for psychosis according to their subsequent clinical outcomes. Seventy-six CHR participants as defined using the Comprehensive Assessment of At-Risk Mental States (CAARMS) and 31 healthy controls (HC) were studied while performing a novelty salience fMRI task that engaged an a priori hippocampal-striatal-midbrain circuit of interest. The CHR sample was then followed clinically for a mean of 59.7 months (~5 y), when clinical outcomes were assessed in terms of transition (CHR-T) or non-transition (CHR-NT) to psychosis (CAARMS criteria): during this period, 13 individuals (17%) developed a psychotic disorder (CHR-T) and 63 did not. Functional activation and effective connectivity within a hippocampal-striatal-midbrain circuit were compared between groups. In CHR individuals compared to HC, hippocampal response to novel stimuli was significantly attenuated (P = .041 family-wise error corrected). Dynamic Causal Modelling revealed that stimulus novelty modulated effective connectivity from the hippocampus to the striatum, and from the midbrain to the hippocampus, significantly more in CHR participants than in HC. Conversely, stimulus novelty modulated connectivity from the midbrain to the striatum significantly less in CHR participants than in HC, and less in CHR participants who subsequently developed psychosis than in CHR individuals who did not become psychotic. Our findings are consistent with preclinical evidence implicating hippocampal-striatal-midbrain circuit dysfunction in altered salience processing and the onset of psychosis.

The aim of this review is to assess the potential for neuroimaging measures to facilitate prediction of the onset of psychosis. Research in this field has mainly involved people at 'ultra-high risk' (UHR) of psychosis, who have a very high risk of developing a psychotic disorder within a few years of presentation to mental health services.The review details the key findings and developments in this area to date, and examines the methodological and logistical challenges associated with making A C C E P T E D M A N U S C R I P T ACCEPTED MANUSCRIPT2 predictions in an individual subject in a clinical setting. Key wordsPsychosis prediction; Ultra High-Risk of psychosis; machine learning; Support Vector Machines; multimodal neuroimaging; multicentre neuroimaging studies; graph analysis Psychosis prediction and the ultra high-risk statePsychosis describes a syndrome that includes symptoms such as hallucinations, delusions, disorganised thought, and catatonia Criteria for UHR status include attenuated psychotic symptoms and / or a brief limited intermittent psychotic episode and / or a genetically determined vulnerability, alongside deterioration in social and occupational functioning 7 8 . UHR status comes A C C E P T E D M A N U S C R I P T ACCEPTED MANUSCRIPT3 with the caveat that those who meet UHR status are selectively those who have come into contact with clinical services. This review uses the term UHR throughout.The UHR population is strikingly heterogeneous in terms of clinical outcomes.Follow-up studies 9 10 suggest that 7 years after clinical presentation, approximately a third of UHR subjects will have developed a psychotic disorder, with most transitions occurring in the first 2 years 11. Most of those who do not develop a psychotic disorder will have persistent attenuated symptoms and / or have developed another mental health disorder, whilst 14% will have recovered (see figure 1).Clinical intervention in the UHR group may reduce the likelihood of the onset of a psychotic disorder 12. However, as most UHR subjects do not develop a psychotic disorder, providing preventative treatment to all of those at risk is clinically inefficient. Identifying biomarkers that could be used to stratify the UHR group according to clinical outcome would enable the selective delivery of preventative interventions to the subgroup that would benefit the most.It is difficult to predict clinical outcomes in an UHR subject on the basis of their clinical features at presentation. Although the clinical assessment at presentation has good diagnostic validity for ruling out a future psychotic disorder (meta analytical sensitivity of UHR assessment = 0.96) 13, it has only a modest ability to rule in a future psychotic disorder (meta-analytical specificity of UHR assessment = 0.47) 13.There is thus a need to find other forms of assessment that can improve the specificity of psychosis prediction. Fusar-Poli et al. (2015) 14 and based on data by Lin et al. (2011) 10 . A C C E P T E D M A N U S C R I P T ACCEPTED MANU...

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BackgroundReduction of duration of untreated psychosis (DUP) is the key strategy of early interventions for improving the outcomes of first episode psychosis. Although several controlled interventional studies have been conducted with the aim of reducing DUP, the results are highly inconsistent and conflicting.MethodsThe current study systematically searched Web of Science and Ovid for English original articles investigating interventions adopted to reduce DUP, compared to a control intervention, up to 6th April 2017. 16 controlled interventional studies were retrieved, including 1964 patients in the intervention arm and 1358 in the control arm. The controlled interventions studies were characterised by: standalone first episode psychosis services, standalone clinical high risk services, community interventions, healthcare professional training and multifocus interventions. Random effects meta-analyses were conducted.ResultsThere was no summary evidence that available interventions are successful in reducing DUP during the first episode of psychosis (Hedges’ g = -0.12, 95%CIs -0.25 to 0.01). Subgroup analyses showed no differences within each subgroup, with the exception of clinical high risk services (Hedges’ g = -0.386, 95%CI -0.726 to -0.045). . There was substantial heterogeneity (I2 = 66.4%), most of which was accounted by different definitions of DUP onset (R2=0.88).DiscussionThese negative findings may reflect a parcelled research base in the area, lack of prospective randomized controlled trials (only two randomised cluster designed studies were present) and small sample sizes. Psychometric standardisation of DUP definition, improvement of study design and implementation of preventative strategies seem the most promising avenues for reducing DUP and improving outcomes of first-episode psychosis.

The ability to identify biomarkers of psychosis risk is essential in defining effective preventive measures to potentially circumvent the transition to psychosis. Using samples of people at clinical high risk for psychosis (CHR) and Healthy controls (HC) who were administered a task fMRI paradigm, we used a framework for labelling time windows of fMRI scans as 'integrated' FC networks to provide a granular representation of functional connectivity (FC). Periods of integration were defined using the 'cartographic profile' of time windows and k-means clustering, and sub-network discovery was carried out using Network Based Statistics (NBS). There were no network differences between CHR and HC groups. Within the CHR group, using integrated FC networks, we identified a sub-network negatively associated with longitudinal changes in the severity of psychotic symptoms. This sub-network comprised brain areas

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