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BACKGROUND: Specialist early intervention (SEI) service models are designed to treat symptoms, promote social and vocational recovery, prevent relapse, and resource and up-skill patients and their families. The benefits of SEI over the first few years have been demonstrated. While early recovery can be expected to translate to better long-term outcomes by analogy with other illnesses, there is limited evidence to support this from follow-up studies. The current study involves the long-term follow-up of a sub-set of first episode psychosis (FEP) patients, with a range of diagnoses, who were first treated at Orygen's Early Psychosis Prevention and Intervention Centre (EPPIC) between 1998 and 2000. The aim of this paper is to present the methodology for this follow-up study. METHODS: Between January 1998 and December 2000, 786 patients between the ages of 15-29 years were treated at EPPIC, located in Melbourne, Australia. Our cohort consists of 661 people (82 were transferred/discharged and 43 were not diagnosed with a psychotic disorder at time of discharge). The 18-month treatment characteristics of this cohort have been extensively examined in the First Episode Psychosis Outcome Study (FEPOS). The ≥15 year outcomes of this cohort are being examined in this study, known as FEPOS15. RESULTS: Participant follow-up is ongoing. In order to extend and assess broader outcomes of the cohort, data linkage with health-related databases will be conducted. CONCLUSION: This study will provide a comprehensive evaluation of the long-term trajectory of psychotic disorders after treatment for FEP in a SEI service.

Objectives The field of early psychosis has undergone considerable expansion over the last few decades and has a strong evidence base of effectiveness. Like all areas of healthcare, however, early psychosis services need to more consistently deliver higher quality care to achieve better outcomes for patients and families. A national clinical research infrastructure is urgently required to enable the sector to deliver the highest quality care and expand and translate evidence more quickly and efficiently. This paper describes the establishment of the Australian Early Psychosis Collaborative Consortium (AEPCC) that aims to achieve this. Conclusion AEPCC is the first of its kind in Australia (and internationally). It will deliver the required clinical research infrastructure through the implementation of a clinical quality registry, clinical trials and translation network, and lived experience network. AEPCC will provide a critical resource to better understand the state of early psychosis care, and trial new interventions on a scale that has not previously been possible in Australia.

IntroductionEarly onset of bipolar disorder is associated with high rates of psychiatric comorbidity (e.g., anxiety disorders, ADHD, PTSD), high rates of recurrence, and marked impairment in functioning and quality of life. The aim of this analysis was to evaluate the efficacy and safety of lurasidone in bipolar depression in youth and young adult patients (10–30 years old).MethodsData from two 6-week, double-blind, placebo-controlled studies of lurasidone monotherapy for bipolar I depression were pooled for this analysis. In the 1st study, patients 10–17 years old were evaluated using the Children’s Depression Rating Scale–Revised (CDRS-R) and the Clinical Global Impression-Bipolar Severity (CGI-BP-S) depression scale; in the 2nd study, a subgroup of adult patients (18–30 years old) were evaluated by CGI-BP-A, and the MADRS, with the latter being converted to a CDRS-R scores using a validated conversion algorithm.ResultsThe safety population consisted of 465 patients (mean age, 17.1 years; mean age of onset, 14.1; mean CDRS-R total score, 60.8). 400 patients (85.7%) completed the study. For lurasidone vs. placebo, LS mean Week 6 change was -21.4 vs. -15.3 for the CDRS-R total score (PConclusionsIn this post-hoc analysis of two placebo-controlled trials, lurasidone demonstrated clinically meaningful improvement of depressive symptoms in youth and young adults with bipolar depression. Lurasidone was generally safe, well-tolerated, and associated with minimal effects on weight, metabolic parameters, and prolactin.FundingServier Laboratories (Aust.) Pty. Ltd., and Sunovion Pharmaceuticals Inc.

Major depressive disorder is a common, recurrent, disabling and costly disorder that is often severe and/or chronic, and for which non-remission on guideline concordant first-line antidepressant treatment is the norm. A sizeable percentage of patients diagnosed with MDD do not achieve full remission after receiving antidepressant treatment. How to understand or approach these 'refractory', 'TRD' or 'difficult to treat' patients need to be revisited. Treatment resistant depression (TRD) has been described elsewhere as failure to respond to adequate treatment by two different antidepressants. This definition is problematic as it suggests that TRD is a subtype of major depressive disorder (MDD), inferring a boundary between TRD and depression that is not treatment resistant. However, there is scant evidence to suggest that a discrete TRD entity exists as a distinct subtype of MDD, which itself is not a discrete or homogeneous entity. Similarly, the boundary between TRD and other forms of depression is predicated at least in part on regulatory and research requirements rather than biological evidence or clinical utility.This paper aims to investigate the notion of treatment failure in order to understand (i) what is TRD in the context of a broader formulation based on the understanding of depression, (ii) what factors make an individual patient difficult to treat, and (iii) what is the appropriate and individualised treatment strategy, predicated on an individual with refractory forms of depression?Expert contributors to this paper were sought internationally by contacting representatives of key professional societies in the treatment of MDD - World Federation of Societies for Biological Psychiatry, Australasian Society for Bipolar and Depressive Disorders, International Society for Affective Disorders, Collegium Internationale Neuro-Psychopharmacologium and the Canadian Network for Mood and Anxiety Treatments. The manuscript was prepared through iterative editing.The concept of TRD as a discrete subtype of MDD, defined by failure to respond to pharmacotherapy, is not supported by evidence. Between 15 and 30% of depressive episodes fail to respond to adequate trials of 2 antidepressants, and 68% of individuals do not achieve remission from depression after a first-line course of antidepressant treatment. Failure to respond to antidepressant treatment, somatic therapies or psychotherapies may often reflect other factors including; biological resistance, diagnostic error, limitations of current therapies, psychosocial variables, a past history of exposure to childhood maltreatment or abuse, job satisfaction, personality disorders, co-morbid mental and physical disorders, substance use or non-adherence to treatment. Only a subset of patients not responding to antidepressant treatment can be explained through pharmacokinetic or pharmacodynamics mechanisms. We propose that non remitting MDD should be personalised, and propose a strategy of 'deconstructing depression'. By this approach, the clinician considers which factors contribute to making this individual both depressed and 'resistant' to previous therapeutic approaches. Clinical formulation is required to understand the nature of the depression. Many predictors of response are not biological, and reflect a confluence of biological, psychological, and sociocultural factors, which may influence the illness in a particular individual. After deconstructing depression at a personalised level, a personalised treatment plan can be constructed. The treatment plan needs to address the factors that have contributed to the individual's hard to treat depression. In addition, an individual with a history of illness may have a lot of accumulated life issues due to consequences of their illness, and these should be addressed in a recovery plan.A 'deconstructing depression' qualitative rubric does not easily provide clear inclusion and exclusion criteria for researchers wanting to investigate TRD.MDD is a polymorphic disorder and many individuals who fail to respond to standard pharmacotherapy and are considered hard to treat. These patients are best served by personalised approaches that deconstruct the factors that have contributed to the patient's depression and implementing a treatment plan that adequately addresses these factors. The existence of TRD as a discrete and distinct subtype of MDD, defined by two treatment failures, is not supported by evidence.

ObjectiveCognitive impairment occurs in antipsychotic-naïve first-episode psychosis (FEP), but antipsychotics confound interpretation of the longitudinal course of cognition. The primary aim was to disentangle the effects of illness from antipsychotics on cognition over the first 6-months of FEP treatment.MethodsRandomised, triple-blind placebo-controlled trial (Staged Treatment and Acceptability Guidelines in Early Psychosis; STAGES), where cognition was a secondary outcome. Antipsychotic-naïve FEP patients were allocated to receive risperidone/paliperidone (N=38) or placebo (N=40) in addition to intensive psychosocial therapy for 6-months. A healthy control group (N=42) was also recruited. A cognitive battery assessing attention, working memory, processing speed, verbal fluency, cognitive control and verbal paired-associate learning and memory was administered at baseline and 6-months. Twelve- and 24-month follow-up was also conducted.ResultsOver the 6-month trial period, cognitive performance remained stable (working memory, verbal fluency) or improved (attention, processing speed, cognitive control), with no group-by-time interaction evident. The exception was for verbal paired-associate learning and memory, where a significant group-by-time interaction was observed. The placebo and healthy control groups improved, and the medication group deteriorated on immediate paired-associate recall (p=0.039) and delayed cued recall (p=0.005); effect sizes were medium-to-large. Findings were similar when only trial completers were included in the analysis.ConclusionsRisperidone/paliperidone may cause progression of memory impairment in the early months of FEP. Replication is needed in confirmatory trials. The findings support the need for careful consideration of the risks and benefits of various antipsychotics and the importance of accounting for their cognitive effects in longitudinal research.Trial registrationAustralian New Zealand Clinical Trials Registry (http://www.anzctr.org.au/ ACTRN12607000608460).

Objective To investigate the clinical characteristics of tertiary students and non-students attending a specialist clinic for severe mood disorders. Method Medical record audit of clients discharged from the Youth Mood Clinic (YMC). Data extracted included depressive symptomatology, suicidal ideation, self-harm, suicide attempt, tertiary education engagement, drop-out and deferral. Results Data from 131 clients ( M age = 19.58 years, SD = 2.66) were analysed, including 46 tertiary students. Relative to non-students, at intake, tertiary students reported more severe depressive symptomatology ( d = 0.43). They were more likely to experience suicidal ideation at intake ( V = 0.23), and during treatment ( V = 0.18). Tertiary students were also more likely to be living separately to their family of origin ( V = 0.20) but were less likely to have experienced parental separation ( V = 0.19). 21.73% of tertiary students dropped out or deferred study during care. Conclusion In this cohort, those engaged in tertiary education experience more severe depression and more commonly experienced suicidal ideation. These young people require targeted support for their mental health while they undertake tertiary education.

Aim Prevention and early intervention efforts of serious mental illnesses has yielded promising results. However, alongside benefits, several ethical concerns have been raised, including the effects of being identified as being at-risk. In these debates, the voice of parents or carers is conspicuously absent. This is especially concerning as several at-risk interventions are trialled in under-age youth where parents consent on behalf of young people. Therefore, this study aimed to understand carer's experiences of their teenager being identified as at risk for psychosis. Methods Semi-structured interviews were conducted with seven carers who had provided consent for their teenager to participate in a stepped intervention study for youth at-risk for psychosis. Questions explored their experiences regarding having their teenager being identified as at-risk. Transcripts were analysed using thematic analysis. Results We identified five main themes from seven female carers' experiences of risk identification including: (a) recall of risk information was limited, or variable, (b) goal of risk disclosure was perceived to be positive, (c) negative emotions were associated with knowledge of risk, (d) relief from uncertainty and helplessness and (e) effects of risk disclosure were mediated by individual circumstance. Conclusion Overall, the results demonstrate that carers' experience of risk disclosure varied with factors surrounding their individual circumstances, and the process of disclosure. Whilst participants acknowledged potential adverse effects associated with risk disclosure, many still adopted a positive outlook. Tailoring safe and effective disclosure of risk to suit the needs of youth and carers could outweigh the potential risks.

Background Interventions early in the course of bipolar disorder (BD) may have the potential to limit its functional and symptomatic impact. However, the implementation of specific early interventions for BD has been limited which may at least partly be due to the lack of guidelines focused on the early illness stages. We therefore aimed to review the current recommendations for early stage BD from clinical practice guidelines. Methods We searched PubMED and PsychINFO for clinical guidelines for BD published in the ten years prior to 1 November 2018. Recommendations from identified guidelines that addressed early stage BD or first episode mania were consolidated and compared. We also reviewed the guidelines relating to adolescents with BD to complement the guidelines related to those in the early illness course. Results We identified fourteen international and national guidelines on BD or affective psychoses. Most guidelines contained a separate section on adolescents, but only a few referred specifically to early stage BD. There were no consistent recommendations for early stage disorder, except with respect to the indications for maintenance medication treatments. For adolescents, there was a consistent recommendation for the use of second generation antipsychotics for treating acute mania. Limitation The main limitation is that the identified guidelines did not include primary data that clearly separated illness and developmental stages. Conclusions There is a lack of emphasis on early BD among widely-respected current clinical guidelines, likely reflecting the dearth of primary data. Future evidence or consensus-based recommendations could significantly inform clinical practice for this population.

The care of people with first-episode mania has been overlooked in comparison with the care of patients with other non-affective psychoses, despite evidence suggesting targeted treatments might be of benefit for this patient group. In this Personal View, we outline the general epidemiology of first-episode mania in the context of bipolar disorder, the natural history of mania (with an emphasis on its recurrent nature), current evidence for pharmacological, psychological, and service-level interventions, current guidelines for the treatment of first-episode mania, and provide a patient's point of view of the care pathway (appendix). We note the paucity of high-quality evidence for interventions in first-episode mania and the lack of agreement among treatment guidelines in relation to treatment, especially maintenance treatment. We suggest that, based on high morbidity and clinical need, research evidence to inform guideline development is necessary, and in the interim, clearer guidance on treatment and diagnosis should be given; specifically, we have suggested that patients should be cared for within a first-episode psychosis service, when such a service exists.

Objectives Psychotic disorder incidence varies geographically and is associated with neighbourhood characteristics, including social deprivation, population density, unemployment, social capital or social fragmentation. Yet it is not known whether these findings are applicable to Australia's unique geography. This study aimed to determine whether the incidence of first episode psychosis (FEP) varies according to neighbourhood characteristics in an Australian cohort. Method This study included all young people, aged 15 to 24, with an FEP who attended Orygen Youth Health in Melbourne, from a geographically defined catchment area encompassing Northern and Western Melbourne, over a 44-month period. Neighbourhood demographic data was collected from the 2011 Australian National Census. Negative binomial regression was used to determine incidence rate ratios controlled for age, sex and migrant status. Results A total of 747 young people had an FEP during the 44-month study period and 722 were included in this study. Of these, 58.0% were males and 67.9% had a non-affective psychotic disorder; the mean age of the cohort was 19.1 years. The incidence of FEP in young people aged 15 to 24 in the catchment area was 123.2 per 100,000 person-years. There was a higher incidence of FEP in neighbourhoods of greatest social deprivation (IRR = 1.65, CI = 1.06–2.51, p = .02), highest unemployment (IRR = 1.56, CI = 1.04–2.35, p = .03) and above average social fragmentation (IRR = 1.42, CI = 1.02–1.97, p = .04), when controlled for age, sex and migrant status. Conclusions This study highlights variation in psychotic disorder incidence and the need for this disparity to be reflected in appropriate resource allocation.

Aim Young people with bipolar disorder (BD) commonly experience reduced quality of life, persistent symptoms and impaired functional recovery despite often superior school performance. Compromised long-term functioning can ensue. There is evidence that psychological therapies alongside pharmacology may be more efficacious earlier in the course of the disorder. Intervention in the early stages may thus reduce the burden and risk associated with BD and mitigate the impact of the disorder on normal developmental trajectories. To date, however, the availability of evidence-based psychological therapies for young people with early BD is limited. Furthermore, there are no large-scale randomized controlled trials (RCTs) of such interventions. Methods The study is a prospective, single-blind, RCT examining the effectiveness of an adjunctive individualized and manualized psychological intervention, compared with treatment as usual within youth-specific early intervention services. The REsearch into COgnitive and behavioural VERsatility (RECOVER) intervention is delivered over a 6-month period. About 122 young people in the early stages of BD-I (at least one manic episode in the previous 2 years, with no more than five lifetime treated/untreated manic or hypomanic episodes) will be recruited. The assessments will occur at baseline, 3, 6 (primary endpoint, end of treatment), 9, 12, 15 and 18 months. Results Recruitment will commence in January 2019 and is anticipated to occur over a 3.5-year period. Conclusions To date, there are no evidence-based psychological therapies tailored to young people with early BD. We will test whether early psychological intervention in the course of BD can reduce the symptomatic, psychological, vocational and social impacts that are seen in entrenched disorder.

Objectives: To clarify the clinical features preceding the onset of bipolar disorder (BD) has become a public health priority for the prevention of high morbidity and mortality. BD remains frequently under‐ or misdiagnosed, and under‐ or mistreated, often for years. Methods: We assessed the predictive value of precursors and prodromes of BD. We assessed precursors of first‐lifetime manic or hypomanic episodes with/without mixed features in retrospective and prospective studies. The task force evaluated and summarized separately assessments of familial risk, premorbid personality traits, retrospective, and prospective studies. Results: Cyclothymic features, a family history of BD, retrospectively reported at‐ tenuated manic symptoms, prospectively identified subthreshold symptoms of hypomania, recurrence of depression, panic anxiety and psychotic features, have been identified as clinical precursors of BD. The prodromal symptoms like [hypo] mania often appears to be long enough to encourage early identification and timely intervention. Conclusions: The predictive value of any risk factor identified remains largely un‐ known. Prospective controlled studies are urgently needed for prevention and ef‐ fective treatment.

Background Community treatment orders (CTOs) are a controversial form of involuntary treatment for individuals affected by mental health disorders and yet little is known about the use of CTOs in first presentations. Therefore, this study aimed to determine the rates, determinants and outcomes associated with the use of CTOs in young people with a first episode of psychosis (FEP). Methods This epidemiological cohort study included all individuals aged 15–24 who presented with a FEP to the Early Psychosis Prevention and Intervention Centre (EPPIC) in Melbourne between 01.01.2011 and 31.12.13. Results A total of 544 young people presented with a FEP during the study period and of these, 93 (17.3%) were subject to a CTO during their episode of care. A total of 69.7% of CTOs were commenced after the first three months of treatment and the median duration of CTOs was 168.5 days. Males, a diagnosis of a schizophrenia spectrum disorder and a concurrent substance abuse disorder were associated with the use of CTOs. Additionally, young people with more severe positive psychotic symptoms were more likely to be subject to a CTO. At the time of discharge, only 38.7% of those subject to a CTO were in education or employment compared to 65.4% of those who had not been subject to a CTO. Conclusions The majority of CTOs are commenced after at least three months of treatment, however the optimal timing of CTO implementation needs to be determined. The poor functioning of young people on a CTO should be the focus of future interventional studies.

Cognitive impairments are a core feature of first-episode psychosis (FEP), arising before illness onset and antipsychotic exposure. Individuals with chronic psychosis experience poorer physical health while taking antipsychotic medication, but health disparities may be evident at FEP onset, prior to antipsychotic exposure. Given the links between cognition and physical health in healthy populations, the aim was to explore whether cognition and physical health are associated in FEP, which could inform early physical health interventions for cognition in FEP. Participants were aged 15 to 25 and included 86 individuals experiencing FEP with limited antipsychotic exposure and duration of untreated psychosis of ≤six months, and 43 age- and sex-matched controls. Individuals with FEP performed significantly poorer than controls in most cognitive domains (Cohen's d = 0.38 to 1.59). Groups were similar in metabolic health measures, excluding a significantly faster heart rate in FEP (d = 0.68). Through hierarchical regression analyses, we found that in the overall sample, BMI was negatively related to current IQ after controlling for education and group (FEP/control). Relationships between BMI and cognition were consistent across the FEP and healthy control groups. In FEP, current IQ and working memory were negatively correlated with lipid profiles. Findings suggest that in FEP, impaired cognition is exhibited earlier than physical health problems, and that compared to controls, similar relationships with cognition are demonstrated. Causal pathways and trajectories of relationships between health and cognition in FEP require investigation, especially as antipsychotic medications are introduced. The findings have implications for cognitive and health interventions.

OBJECTIVE: There is a lack of existing research regarding young people with bipolar I disorder (BD-I) and psychotic features, who are not in education, employment, and training (NEET). Thus, the aims of the study were to: (a) establish rates of NEET at service entry to a specialist early intervention service; (b) delineate premorbid and current variables associated with NEET status at service entry and (c) examine correlates of NEET status at discharge. METHOD: Medical file audit methodology was utilized to collect information on 118 patients with first episode psychotic mania treated at the Early Psychosis Prevention and Intervention Centre (EPPIC), Melbourne, Australia. NEET status was determined using the modified vocation status index (MVCI). Bivariate and multivariable logistic variables were used to examine relationships between premorbid, service entry and treatment variables, and NEET status at service entry and discharge. RESULTS: The NEET rate was 33.9% at service entry, and 39.2% at discharge. Variables associated with NEET status at service entry were premorbid functioning and polysubstance use. NEET status at service entry was the only significant correlate of NEET status at discharge. When service entry NEET was taken out of the model, substance use during treatment was predictive of NEET status at discharge. CONCLUSIONS: NEET status at service entry was related to a history of premorbid decline, and risk factors such as substance use and forensic issues. NEET status can decline during treatment, and utility of vocational intervention programs specifically for BD, in addition to specialist early intervention, needs to be examined.

Aim Personality disorder is a common co-occurrence ('comorbidity') among patients with bipolar disorder and appears to affect outcome negatively. However, there is little knowledge about the impact of this comorbidity in the early phases of bipolar disorder. We examined the prevalence and effect of personality disorder co-occurrence on outcome in a cohort of youth with first episode mania with psychotic features. Methods Seventy-one first episode mania patients, aged 15-29, were assessed at baseline, 6, 12, and 18 months as part of a randomized controlled trial of olanzapine and chlorpromazine as add-on to lithium in first episode mania with psychotic features. The current study involved secondary analysis of trial data. Results A co-occurring clinical personality disorder diagnosis was present in 16.9% of patients. Antisocial and narcissistic personality disorders were the most common diagnoses. Patients with co-occurring personality disorder had higher rates of readmission to hospital, lower rates of symptomatic recovery and poorer functional levels at 6 months, but these differences disappeared after 12 and 18 months. Conclusions In the early phase of bipolar disorder, patients with personality disorder comorbidity display delayed symptomatic and functional recovery and increased likelihood to need hospital readmissions. These observations suggest that routine assessment for personality disorder and specific interventions are important in order to improve short-term treatment efficacy in this subgroup.

Background The impact of guideline concordance on naturalistic maintenance treatment outcomes in BD is not known. We sought to evaluate the effect of guideline-concordant care on symptomatic, course and functional outcomes in youth with early-stage BD-I. Methods In this file audit study, we examined the prospective course of 64 clients with first treatment seeking manic episode of BD-I. Eighteen-month outcome measures included Clinical Global Impressions Scale - Bipolar Version (CGI-BP), Social and Occupational Functioning Assessment Scale (SOFAS) and number of relapses. Correlations and hierarchical linear regressions were used to examine the relationships between guideline concordance and outcomes, while controlling for potential confounders. Results Although higher guideline-concordant care in the maintenance phase was associated with a higher discharge CGI-BP score and thus worse outcome, baseline CGI-BP and insight were more predictive of illness severity at follow-up than guideline concordance. There was no association with SOFAS and guideline-concordant care at follow-up. Greater concordance with maintenance medication guideline statements was also associated with greater number of relapses even after controlling for sex, medication adherence, duration of care and baseline illness severity. Limitations This study was limited by sample size and its single pool of clients which may limit generalizability. Conclusions Contrary to our hypotheses, higher guideline concordance was associated with worse outcomes, although this relationship was moderated by the client's illness characteristics, severity and insight. More unwell youth with poor insight, greater severity, and mixed/rapid cycling features may need other interventions or modified guidelines.

Most psychiatric disorders develop during adolescence and young adulthood and are preceded by a phase during which attenuated or episodic symptoms and functional decline are apparent. The introduction of the ultra-high risk (UHR) criteria two decades ago created a new framework for identification of risk and for pre-emptive psychiatry, focusing on first episode psychosis as an outcome. Research in this paradigm demonstrated the comorbid, diffuse nature of emerging psychopathology and a high degree of developmental heterotopy, suggesting the need to adopt a broader, more agnostic approach to risk identification. Guided by the principles of clinical staging, we introduce the concept of a pluripotent at-risk mental state. The clinical high at risk mental state (CHARMS) approach broadens identification of risk beyond psychosis, encompassing multiple exit syndromes such as mania, severe depression, and personality disorder. It does not diagnostically differentiate the early stages of psychopathology, but adopts a “pluripotent” approach, allowing for overlapping and heterotypic trajectories and enabling the identification of both transdiagnostic and specific risk factors. As CHARMS is developed within the framework of clinical staging, clinical utility is maximized by acknowledging the dimensional nature of clinical phenotypes, while retaining thresholds for introducing specific interventions. Preliminary data from our ongoing CHARMS cohort study (N = 114) show that 34% of young people who completed the 12-month follow-up assessment (N = 78) transitioned from Stage 1b (attenuated syndrome) to Stage 2 (full disorder). While not without limitations, this broader risk identification approach might ultimately allow reliable, transdiagnostic identification of young people in the early stages of severe mental illness, presenting further opportunities for targeted early intervention and prevention strategies.

Among the diverse risk factors for psychosis, clinical markers are the most commonly used in research settings and clinical practice. Such markers have been studied in high-risk populations such as participants with a familial history of psychosis or those with “basic symptoms” or a syndrome of clinical or ultra high risk. A range of clinical risk factors have been identified in these populations including subtypes of psychotic symptoms such as disorganization and unusual thought content; markers of general and social functioning; family history of psychosis; early-life trauma; obstetric complications; and cannabis abuse. These factors should be considered in terms of their impact on the risk of diverse future outcomes including psychotic symptomatology, psychosocial functioning, and other mental disorders. Consideration of factors that affect the base rates of such outcomes in individual populations and how these clinical risk factors affect these rates are important for clinicians and researchers in interpreting risk.

This triple-blind (participants, clinicians, and researchers) randomized controlled noninferiority trial examined whether intensive psychosocial intervention (cognitive-behavioral case management, CBCM) for first-episode psychosis (FEP) in 15–25 year-olds managed in a specialized early intervention for psychosis service was noninferior to usual treatment of antipsychotic medication plus CBCM delivered during the first 6 months of treatment. To maximize safety, participants were required to have low levels of suicidality and aggression, a duration of untreated psychosis (DUP) of less than 6 months, and be living in stable accommodation with social support. The primary outcome was level of functioning as assessed by the Social and Occupational Functioning Scale (SOFAS) at 6 months. Ninety young people were randomized by computer, 46 to placebo, and 44 antipsychotic medication and 33% of those who commenced trial medication completed the entire 6-month trial period. On the SOFAS, both groups improved, and group differences were small and clinically trivial, indicating that treatment with placebo medication was no less effective than conventional antipsychotic treatment (mean difference = −0.2, 2-sided 95% confidence interval = −7.5 to 7.0, t = 0.060, P = .95). Within the context of a specialized early intervention service, and with a short DUP, the immediate introduction of antipsychotic medication may not be required for all cases of FEP in order to see functional improvement. However, this finding can only be generalized to a very small proportion of FEP cases at this stage, and a larger trial is required to clarify whether antipsychotic-free treatment can be recommended for specific subgroups of those with FEP. Trial Registration: ACTRN12607000608460 (www.anzctr.org.au).

Background Clinical guidelines recommend maintenance treatment with antipsychotic medication for one to two years following remission of symptoms after a first episode of psychosis. However, recent research has suggested that this may not be indicated. Consistent predictors of outcome would be beneficial to guide clinicians as to which individuals are likely to have a successful discontinuation. Objectives This study reviews the literature with the aim of identifying demographic and clinical predictors of either relapse or continued remission in those with a first episode of psychosis following discontinuation of antipsychotic medication. Methodology Data Sources: A systematic search of PubMed, CINAHL, and PsychInfo databases was performed. Eligibility Criteria: Cohort, case-control and clinical trials that were published in English, included participants with a first episode of psychosis, and examined clinical and demographic predictors of relapse or continued remission after antipsychotic discontinuation. Results Eleven studies fulfilled inclusion criteria. No positive findings were replicated across cohorts. Predictors of relapse: male sex, unemployment, prior psychiatric admission, premorbid adjustment, childhood isolation, premorbid functioning, schizoid-schizotypal traits, schizophrenia diagnosis, concomitant medication, and more severe negative symptoms. Some positive findings must be interpreted in the context of conflicting and replicated negative findings: sex, employment status, level of education, premorbid functioning, symptom severity, and schizophrenia diagnosis. Other replicated non-predictive findings: age, ethnicity, marital status, family history, disorganized thoughts, affective symptoms, cannabis abuse, clinical global impression, social integration, duration and dose of antipsychotic treatment, and compliance. Conclusion No positive findings have been replicated across study cohorts. Non-predictive findings have been replicated.

Background There is uncertainty about the required duration of long-term antipsychotic maintenance medication after a first episode of psychosis. Robust predictors of relapse after discontinuation are yet to be identified. The present study aimed to determine the proportion of young people who discontinue their antipsychotic medication after a first episode of psychosis, the proportion who experience relapse, and predictors of relapse. Methods A retrospective study of all individuals presenting to the Early Psychosis Prevention and Intervention Centre between 01/01/11 and 31/12/13 was conducted. A Cox regression analysis was conducted to identify predictors of relapse. Results A total of 544 young people with a FEP were included. A trial of discontinuation was undertaken by 61% of the cohort. Median duration of antipsychotic medication prior to first trial of discontinuation was 174.50 days. Amongst those trialing discontinuation, 149 (45.8%) experienced relapse in a median follow-up time post discontinuation of 372 days. On multivariate analysis, predictors of relapse were a diagnosis of cannabis abuse disorder (HR: 1.40), and longer duration of antipsychotic medication (HR: 1.05). Conclusion Antipsychotic discontinuation frequently occurs earlier than guidelines recommend. Individuals with a diagnosis of cannabis abuse are more likely to experience relapse and addressing this substance abuse prior to discontinuation could possibly reduce relapse rates.

Introduction Psychosis and mania share conceptual, genetic and clinical features, which suggest the possibility that they have common antecedents. Participants identified to be at-risk for psychosis might also be at-risk for mania. We aimed to identify the rate and predictors of transition to mania in a cohort of youth with clinical or familial risk for psychosis. Methods Among a cohort of 416 young people with an at-risk mental state for psychosis defined using the Ultra-High-Risk (UHR) criteria, 74.7% were followed up between 5 and 13 years from their baseline assessment. We undertook a matched case-control examination of those who developed mania over the follow-up period compared to those who did not develop mania or psychosis. Transition to mania was determined using either a structured clinical interview, or diagnoses from a state-wide public mental health contact registry. Clinical characteristics and risk factors were examined at baseline using information from structured interviews, clinical file notes, rating scales and unstructured assessments. Results Eighteen participants developed mania (UHR-Manic transition or UHR-M, 4.3%). In comparison with participants matched on age, gender and baseline-study who developed neither mania nor psychosis, more UHR-M participants had subthreshold manic symptoms or were prescribed antidepressants at baseline. They also had lower global functioning. Discussion In addition to the UHR criteria, features such as subthreshold manic symptoms and antidepressant use may help identify at-risk groups that predict the onset of mania in addition to transition to psychosis. Presence of manic symptoms may also indicate syndrome specificity early in the prodromal phase.

Here, we report cysteamine derived nitrogen and sulfur co-doped carbon dots (Cy@CD) for imaging pathogenic bacteria and human buccal epithelial cells. The Cy@CD was synthesized using one-step simple microwave-assisted hydrothermal synthesis with precursors, namely, cysteamine and 50X TAE buffer. The spectroscopic characterization of Cy@CD showed (λex/λem) at 350/434 nm with a decent quantum yield of 13.2%. Cy@CD was deployed in tagging bacterial cells such as E. coli, S. aureus, P. aeruginosa and B. subtilis and human buccal epithelial cells. The multicolour emissive Cy@CD tagged microbial cells were also cross-validated by fluorometry analysis. The fluorescent Cy@CD could be used as an ideal substitute for the harmful synthetic fluorescent stain in cell imaging applications.

Aim The development of the ultra-high risk (UHR) criteria for psychosis created a new paradigm for the prevention research in psychiatry. Since (1) prevention research faces the challenge of achieving adequate statistical power when focusing on single low-incidence syndromes and (2) early clinical phenotypes are overlapping and non-specific, this study broadens the UHR state beyond psychosis as an outcome. The CHARMS (clinical high at-risk mental state) study aims to prospectively validate a set of trans-diagnostic criteria to identify help-seeking young people at risk of developing a range of serious mental illnesses. Methods This paper describes the methodology of the CHARMS study, which involves applying the CHARMS criteria to a cohort of help-seeking young people aged 12 to 25 attending youth mental health services in Melbourne. New referrals meeting the CHARMS criteria are allocated to the CHARMS+ group; referrals not meeting CHARMS threshold are allocated to CHARMS- group (control group); referrals meeting criteria for a full-threshold disorder are excluded. Transition status and clinical and functional outcomes are re-assessed at 6 and 12 months. Conclusions This study will be the first to introduce and validate clinical criteria to identify a broader at-risk patient population, which may facilitate young people's access to clinical services and early treatment by reducing the reliance on "caseness" defined according to current diagnostic categories being required for service entry. These criteria may introduce a new, trans-diagnostic approach for understanding risk factors and pathogenic mechanisms that drive the onset of severe mental illness and the next generation of preventive intervention trials.

Illness staging is widely utilized in several medical disciplines to help predict course or prognosis, and optimize treatment. Staging models in psychiatry in general, and bipolar disorder in particular, depend on the premise that psychopathology moves along a predictable path: an at‐risk or latency stage, a prodrome progressing to a first clinical threshold episode, and one or more recurrences with the potential to revert or progress to late or end‐stage manifestations. The utility and validity of a staging model for bipolar disorder depend on its linking to clinical outcome, treatment response and neurobiological measures. These include progressive biochemical, neuroimaging and cognitive changes, and potentially stage‐specific differences in response to pharmacological and psychosocial treatments. Mechanistically, staging models imply the presence of an active disease process that, if not remediated, can lead to neuroprogression, a more malignant disease course and functional deterioration. Biological elements thought to be operative in bipolar disorder include a genetic diathesis, physical and psychic trauma, epigenetic changes, altered neurogenesis and apoptosis, mitochondrial dysfunction, inflammation, and oxidative stress. Many available agents, such as lithium, have effects on these targets. Staging models also suggest the utility of stage‐specific treatment approaches that may not only target symptom reduction, but also impede illness neuroprogression. These treatment approaches range from prevention for at‐risk individuals, to early intervention strategies for prodromal and newly diagnosed individuals, complex combination therapy for rapidly recurrent illness, and palliative‐type approaches for those at chronic, late stages of illness. There is hope that prompt initiation of potentially disease modifying therapies may preclude or attenuate the cognitive and structural changes seen in the later stages of bipolar disorder. The aims of this paper are to: a) explore the current level of evidence supporting the descriptive staging of the syndromal pattern of bipolar disorder; b) describe preliminary attempts at validation; c) make recommendations for the direction of further studies; and d) provide a distillation of the potential clinical implications of staging in bipolar disorder within a broader transdiagnostic framework.

Background Premorbid characteristics may help predict the highly variable functional and illness outcomes of young people with early stage Bipolar Disorder (BD). We sought to examine the relationships between premorbid adjustment and short to medium-term outcomes after a first treated episode of mania. Methods We examined the baseline and 18-month follow-up characteristics of 117 participants with first episode of mania, treated at two tertiary early intervention services in Melbourne, Australia. The baseline demographic, family history, diagnoses, comorbidity and clinical features were determined using unstructured questionnaires and structured diagnostic interviews. Premorbid adjustment was determined using the Premorbid Adjustment Scale (PAS), the components of which were identified using a principal component analysis. Eighteen-month follow-up outcome measures included the Clinical Global Impressions scale, Social and Occupational Functioning Assessment Scale and the Heinrichs’ Quality of Life Scale (QLS). Correlations and linear regressions were utilised to examine the relationships between component scores and outcomes, while controlling for baseline and follow-up confounders. Results The social adjustment component of the PAS correlated with the interpersonal relations ( r s = −0.46, p r s =−0.39, p = 0.004). Premorbid adjustment did not predict illness severity or objective functioning. Limitations Lack of information on cognition, personality factors and prodromal symptoms limited the assessment of their impact on outcomes. Conclusions Impairments in domains of premorbid adjustment may be early markers of persistent difficulties in social and vocational functioning and may benefit from targeted interventions.

Most patients with first episode psychosis (FEP) are neither studying nor employed (have a poor functional status) when first accessing care. Knowledge of the characteristics of patients with poor functioning and the features influencing functional status over time may pave the way to better treatment. A medical file audit was used to collect data on premorbid, entry, treatment and 18-month outcome characteristics on 661 FEP patients who consecutively attended the Early Psychosis Prevention and Intervention Centre, Melbourne, Australia, between 1998 and 2000. Functional status was ascertained using the modified vocational status index and was rated at baseline (poor or good) and according to its evolution over the treatment period (stable good, stable poor, deteriorating or improved functional status). 52.0% of patients had a poor functional status at service entry. They were more likely to be male with a non-affective psychosis. They also had lower levels of premorbid global functioning and education, and were more likely to have self-reported histories of learning disability, forensic issues, traumatic experiences and substance use. At service entry, they had more severe symptoms and poorer global functioning. 37% of these patients maintained a poor functional status at discharge, and 18% of those with a good functional status at service entry experienced a decline. Although psychosocial interventions might assist a young person with FEP with working towards functional goals, for some, the impact of factors such as ongoing substance use and forensic issues on functional status needs to be addressed.

BACKGROUND Mental ill-health is the leading cause of disability worldwide. Moreover, 75% of mental health conditions emerge between the ages of 12 and 25 years. Unfortunately, due to lack of resources and limited engagement with services, a majority of young people affected by mental ill-health do not access evidence-based support. To address this gap, our team has developed a multimodal, scalable digital mental health service (Enhanced Moderated Online Social Therapy [MOST+]) merging real-time, clinician-delivered web chat counseling; interactive user-directed online therapy; expert and peer moderation; and peer-to-peer social networking. OBJECTIVE The primary aim of this study is to ascertain the feasibility, acceptability, and safety of MOST+. The secondary aims are to assess pre-post changes in clinical, psychosocial, and well-being outcomes and to explore the correlations between system use, perceived helpfulness, and secondary outcome variables. METHODS Overall, 157 young people seeking help from a national youth e-mental health service were recruited over 5 weeks. MOST+ was active for 9 weeks. All participants had access to interactive online therapy and integrated web chat counseling. Additional access to peer-to-peer social networking was granted to 73 participants (46.5%) for whom it was deemed safe. The intervention was evaluated via an uncontrolled single-group study. RESULTS Overall, 93 participants completed the follow-up assessment. Most participants had moderate (52/157, 33%) to severe (96/157, 61%) mental health conditions. All a priori feasibility, acceptability, and safety criteria were met. Participants provided mean scores of ≥3.5 (out of 5) on ease of use (mean 3.7, SD 1.1), relevancy (mean 3.9, SD 1.0), helpfulness (mean 3.5, SD 0.9), and overall experience (mean 3.9, SD 0.8). Moreover, 98% (91/93) of participants reported a positive experience using MOST+, 82% (70/93) reported that using MOST+ helped them feel better, 86% (76/93) felt more socially connected using it, and 92% (86/93) said they would recommend it to others. No serious adverse events or inappropriate use were detected, and 97% (90/93) of participants reported feeling safe. There were statistically significant improvements in 8 of the 11 secondary outcomes assessed: psychological distress (d=−0.39; Pd=−0.44; Pd=0.51; Pd=−0.29; Pd=−0.23; P=.04), social support (d=0.30; Pd=0.36; P=.001), and self-competence (d=0.30; P CONCLUSIONS MOST+ is a feasible, acceptable, and safe online clinical service for young people with mental ill-health. The high level of perceived helpfulness, the significant improvements in secondary outcomes, and the correlations between indicators of system use and secondary outcome variables provide initial support for the therapeutic potential of MOST+. MOST+ is a promising and scalable platform to deliver standalone e-mental health services as well as enhance the growing international network of face-to-face youth mental health services.

Background Inflammation contributes to the pathophysiology of major depressive disorder (MDD), and anti-inflammatory strategies might therefore have therapeutic potential. This trial aimed to determine whether adjunctive aspirin or rosuvastatin, compared with placebo, reduced depressive symptoms in young people (15–25 years). Methods YoDA-A, Youth Depression Alleviation with Anti-inflammatory Agents, was a 12-week triple-blind, randomised, controlled trial. Participants were young people (aged 15–25 years) with moderate to severe MDD (MADRS mean at baseline 32.5 ± 6.0; N = 130; age 20.2 ± 2.6; 60% female), recruited between June 2013 and June 2017 across six sites in Victoria, Australia. In addition to treatment as usual, participants were randomised to receive aspirin (n = 40), rosuvastatin (n = 48), or placebo (n = 42), with assessments at baseline and weeks 4, 8, 12, and 26. The primary outcome was change in the Montgomery-Åsberg Depression Rating Scale (MADRS) from baseline to week 12. Results At the a priori primary endpoint of MADRS differential change from baseline at week 12, there was no significant difference between aspirin and placebo (1.9, 95% CI (− 2.8, 6.6), p = 0.433), or rosuvastatin and placebo (− 4.2, 95% CI (− 9.1, 0.6), p = 0.089). For rosuvastatin, secondary outcomes on self-rated depression and global impression, quality of life, functioning, and mania were not significantly different from placebo. Aspirin was inferior to placebo on the Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q-SF) at week 12. Statins were superior to aspirin on the MADRS, the Clinical Global Impressions Severity Scale (CGI-S), and the Negative Problem Orientation Questionnaire scale (NPOQ) at week 12. Conclusions The addition of either aspirin or rosuvastatin did not to confer any beneficial effect over and above routine treatment for depression in young people. Exploratory comparisons of secondary outcomes provide limited support for a potential therapeutic role for adjunctive rosuvastatin, but not for aspirin, in youth depression. Trial registration Australian New Zealand Clinical Trials Registry, ACTRN12613000112763. Registered on 30/01/2013.

Background First episode psychosis (FEP) may lead to a progressive, potentially disabling and lifelong chronic illness; however, evidence suggests that the illness course can be improved if appropriate treatments are given at the early stages. Nonetheless, the efficacy of antipsychotic medications is suboptimal, particularly for negative and cognitive symptoms, and more efficacious and benign treatments are needed. Previous studies have shown the antioxidant amino acid N-acetyl cysteine (NAC) reduces negative symptoms and improves functioning in chronic schizophrenia and bipolar disorder. Research is scarce as to whether NAC is beneficial earlier in the course of illness. The primary aim of this study is to determine the efficacy of treatment with adjunctive NAC (2g/day for 26 weeks) compared with placebo to improve psychiatric symptoms in young people experiencing FEP. Secondary aims are to explore the neurobiological mechanisms underpinning NAC and how they relate to various clinical and functional outcomes at 26- and 52-week follow-up. Methods ENACT is a 26-week randomised controlled trial of adjunctive NAC versus placebo, with a 26-week non-treatment follow-up period, for FEP. We will be recruiting 162 young people aged 15-25 years who have recently presented to, and are being treated at, the Early Psychosis Prevention and Intervention Centre, Melbourne, Australia. The primary outcome is the Total Score on the Positive and Negative Syndrome Scale which will be administered at baseline, and weeks 4, 8, 12, 26 (primary endpoint), and 52 (end of study). Secondary outcomes include: symptomatology, functioning, quality of life, neurocognition, blood-derived measures of; inflammation, oxidative and nitrosative stress, and magnetic resonance spectroscopy measures of glutathione concentration. Discussion Targeted drug development for FEP to date has generally not involved the exploration of neuroprotective agents. This study has the potential to offer a new, safe, and efficacious treatment for people with FEP, leading to better treatment outcomes. Additionally, the neuroprotective dimension of this study may lead to a better long-term prognosis for people with FEP. It has the potential to uncover a novel treatment that targets the neurobiological mechanisms of FEP and, if successful, will be a major advance for psychiatry.

Background First-episode psychosis (FEP) may lead to a progressive, potentially disabling and lifelong chronic illness; however, evidence suggests that the illness course can be improved if appropriate treatments are given at the early stages. Nonetheless, the efficacy of antipsychotic medications is suboptimal, particularly for negative and cognitive symptoms, and more efficacious and benign treatments are needed. Previous studies have shown that the antioxidant amino acid N-acetylcysteine (NAC) reduces negative symptoms and improves functioning in chronic schizophrenia and bipolar disorder. Research is scarce as to whether NAC is beneficial earlier in the course of illness. The primary aim of this study is to determine the efficacy of treatment with adjunctive NAC (2 g/day for 26 weeks) compared with placebo to improve psychiatric symptoms in young people experiencing FEP. Secondary aims are to explore the neurobiological mechanisms underpinning NAC and how they relate to various clinical and functional outcomes at 26- and 52-week follow-ups. Methods/design ENACT is a 26-week, randomised controlled trial of adjunctive NAC versus placebo, with a 26-week non-treatment follow-up period, for FEP. We will be recruiting 162 young people aged 15–25 years who have recently presented to, and are being treated at, the Early Psychosis Prevention and Intervention Centre, Melbourne, Australia. The primary outcome is the Total Score on the Positive and Negative Syndrome Scale which will be administered at baseline, and weeks 4, 8, 12, 26 (primary endpoint), and 52 (end of study). Secondary outcomes include: symptomatology, functioning, quality of life, neurocognition, blood-derived measures of: inflammation, oxidative and nitrosative stress, and magnetic resonance spectroscopy measures of glutathione concentration. Discussion Targeted drug development for FEP to date has generally not involved the exploration of neuroprotective agents. This study has the potential to offer a new, safe, and efficacious treatment for people with FEP, leading to better treatment outcomes. Additionally, the neuroprotective dimension of this study may lead to a better long-term prognosis for people with FEP. It has the potential to uncover a novel treatment that targets the neurobiological mechanisms of FEP and, if successful, will be a major advance for psychiatry. Trial registration Australian New Zealand Clinical Trials Registry, ID: ACTRN12618000413224. Registered on 21 March 2018.

Background Specialist early intervention (SEI) service models are designed to treat symptoms, promote social and vocational recovery, prevent relapse, and resource and up skill patients and their families. While the immediate benefits of SEI are clear, and have been demonstrated, the long-term impact of SEI on illness course is less clear. The First Episode Outcome Study involves the long-term follow-up of a representative sample of first episode psychosis patients who were first treated at the Early Psychosis Prevention and Intervention Centre (EPPIC) between 1998 and 2000. In this presentation the preliminary data on physical health outcomes are reported. Methods Between January 1998 and December 2000, 661 patients between the ages of 15–29 years were treated at the Early Psychosis Prevention and Intervention Centre, Melbourne Australia. The 18-month treatment characteristics of this cohort have been extensively examined in the First Episode Psychosis Outcome Study (FEPOS). The long-term outcomes of this cohort are now being examined in a new study (known as FEPOS15). Results The rates of self-report physical health problems in 100 participants 15 years after being treated for a first episode psychosis were significant for high cholesterol (41%), asthma (33.7%), chronic pain (25.3%), allergies (19.3%), respiratory problems (16.9%) anemia (12.2%), arthritis (12.0%), hepatitis C (10.8%) and diabetes (6.3%). Cardiovascular problems were also noted including heart attack (2.4%), other heart problems (8.4%), and stroke (3.6%). Sexual health problems are explored. Physical health findings pertaining to Coroners’ findings on those who had died will be also used to describe the long-term impacts of psychotic disorder. Discussion This follow-up study is one of the longest, largest and most comprehensive studies of the multidimensional outcomes of a SEI service for psychosis. The physical health outcomes of individuals 15-years after the first episode psychosis are poor. The importance of monitoring and managing physical health problems in those with psychotic disorder is highlighted.

Summary Background Medication is commonly used to treat youth depression, but whether medication should be added to cognitive behavioural therapy (CBT) as first-line treatment is unclear. We aimed to examine whether combined treatment with CBT and fluoxetine was more effective than CBT and placebo in youth with moderate-to-severe major depressive disorder. Methods The Youth Depression Alleviation–Combined Treatment (YoDA-C) trial was a randomised, double-blind, placebo-controlled, multicentre clinical trial. Participants were aged 15–25 years with moderate-to-severe MDD and had sought care at one of four clinical centres in metropolitan Melbourne, Australia. Patients were randomly assigned (1:1) to receive CBT for 12 weeks, plus either fluoxetine or placebo. Participants began on one 20 mg capsule of fluoxetine or one placebo pill per day. All participants received CBT, delivered by therapists in weekly 50-minute sessions and attended interviews at baseline, and at weeks 4, 8, and 12, during which they completed assessments with research assistants. Participants saw a psychiatrist or psychiatry trainee to complete medical assessments at the same timepoints. The primary outcome was change in the interviewer-rated Montgomery-Asberg Depression Rating Scale (MADRS) score at 12 weeks. The trial was registered with the Australian New Zealand Clinical Trials Registry (ACTRN12612001281886). Findings 153 participants (mean age 19·6 years [SD 2·7]) were enrolled from Feb 20, 2013, to Dec 13, 2016. 77 (50%) patients were allocated to CBT and placebo and 76 (50%) to CBT and fluoxetine. Participants had severe depression at baseline (mean MADRS score 33·6 [SD 5·1] in the CBT and placebo group and 32·2 [5·6] in the CBT and fluoxetine group), with high proportions of participants with anxiety disorder comorbidity (47 [61%] in the CBT and placebo group and 49 [64%] in the CBT and fluoxetine group) and past-month suicidal ideation (55 [71%] in the CBT and placebo group and 59 [78%] in the CBT and fluoxetine group). 59 (77%) participants in the CBT and placebo group and 64 (84%) in the CBT and fluoxetine group completed follow-up at week 12. After 12 weeks of treatment both groups showed a reduction in MADRS scores (−13·7, 95% CI −16·0 to −11·4, in the CBT and placebo group and −15·1, −17·4 to −12·9, in the CBT and fluoxetine group). There was no significant between-group difference in MADRS scores (−1·4, −4·7 to 1·8; p=0·39). There were five suicide attempts in the CBT and placebo group and one suicide attempt in the CBT and fluoxetine group (odds ratio 0·2, 0·0–1·8; p=0·21), and no significant between-group differences for other suicidal behaviours. Interpretation We did not find evidence that the addition of fluoxetine (rather than placebo) to CBT further reduced depressive symptoms in young people with moderate-to-severe MDD. Exploratory analyses showed that the addition of medication might be helpful for patients with comorbid anxiety symptoms and for older youth. Funding Australian National Health and Medical Research Council.

Antipsychotic medication has been the mainstay of treatment for psychotic illnesses for over 60 years. This has been associated with improvements in positive psychotic symptoms and a reduction in relapse rates. However, there has been little improvement in functional outcomes for people with psychosis. At the same time there is increasing evidence that medications contribute to life shortening metabolic and cardiovascular illnesses. There is also uncertainty as to the role played by antipsychotic medication in brain volume changes. Aim The primary aim of the study is, in a population of young people with first-episode psychosis, to compare functional outcomes between an antipsychotic dose reduction strategy with evidence-based intensive recovery treatment (EBIRT) group (DRS+) and an antipsychotic maintenance treatment with EBIRT group (AMTx+) at 24-months follow-up. Methods Our single-blind randomized controlled trial, within a specialist early psychosis treatment setting, will test the whether the DRS+ group leads to better vocational and social recovery than, the AMTx+ group over a 2-year period in 180 remitted first-episode psychosis patients. Additionally, we will examine the effect of DRS+ vs AMTx+ on physical health, brain volume and cognitive functioning. This study will also determine whether the group receiving DRS+ will be no worse off in terms of psychotic relapses over 2 years follow-up. Results This paper presents the protocol, rationale and hypotheses for this study which commenced recruitment in July 2017. Conclusion This study will provide evidence as to whether an antipsychotic dose-reduction recovery treatment leads to improved functioning and safer outcomes in first-episode psychosis patients. In addition, it will be the first-controlled experiment of the effect of exposure to antipsychotic maintenance treatment on brain volume changes in this population.

Aim Early intervention and prevention of serious mental disorders such as bipolar disorder has the promise of decreasing the burden associated with these disorders. With increasing early and preventive intervention efforts among cohorts such as those with a familial risk for bipolar disorder, there is a need to examine the associated ethical concerns. The aim of this review was to examine the ethical issues underpinning the clinical research on pre-onset identification and preventive interventions for bipolar disorder. Methods We undertook a PubMed search updated to November 2014 incorporating search terms such as bipolar, mania, hypomania, ethic*(truncated), early intervention, prevention, genetic and family. Results Fifty-six articles that were identified by this method as well as other relevant articles were examined within a framework of ethical principles including beneficence, non-maleficence, respect for autonomy and justice. The primary risks associated with research and clinical interventions include stigma and labelling, especially among familial high-risk youth. Side effects from interventions are another concern. The benefits of preventive or early interventions were in the amelioration of symptoms as well as the possibility of minimizing disability, cognitive impairment and progression of the illness. Supporting the autonomy of individuals and improving access to stigma-free care may help moderate the potential challenges associated with the risks of interventions. Conclusions Concerns about the risks of early identification and pre-onset interventions should be balanced against the potential benefits, the individuals' right to choice and by improving availability of services that balance such dilemmas.