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...

Background and Hypothesis Treatment response to specific antipsychotic medications is difficult to predict on clinical grounds alone. The current study hypothesizes that the baseline complement pathway activity predicts the treatment response and investigates the relationship between baseline plasma biomarkers with treatment response to antipsychotic medications. Study Design Baseline plasma samples were collected from first episode of psychosis patients (n = 243) from a multi-center clinical trial. The participants were treated with amisulpride for 4 weeks. Levels of complement and coagulation proteins at baseline were measured using both data-dependent and data-independent mass spectrometry approaches. The primary outcome was remission status at 4 weeks and the secondary outcomes included change in psychotic and functional symptoms over the period of treatment. In addition, immunoassays were performed at baseline for complement C1R, as well as for activation markers C4a and sC5b-9. Study Results The plasma level of complement variant C4A was significantly associated with remission at 4 weeks. Moreover, higher levels of several complement and coagulation pathway proteins were associated with a reduction in psychotic symptoms and an improvement in functioning. Immunoassays showed an association of baseline levels of C1R and C4a as well as complement activation marker sC5b-9 levels with treatment response. Conclusion The results demonstrated that the response to antipsychotic treatment might be related to pre-treatment levels of plasma complement and coagulation pathway proteins. This is consistent with independent evidence associating immune dysfunction with the pathophysiology of psychosis. Moreover, these results inform the development of novel therapeutic approaches that target the complement system for psychosis.