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Key Points: Question: What are the optimal type, timing, and sequence of interventions for individuals at ultrahigh risk of psychosis? Findings: In this sequential multiple assignment randomized trial including 342 individuals, a specialized psychological intervention (cognitive-behavioral case management [CBCM]) and a psychopharmacological intervention (CBCM and antidepressant medication) were not more efficacious than control conditions in improving remission and functional recovery. Relapse rates among individuals who remitted were high. Meaning: The findings of this study show that addition of sequentially more specialized psychosocial and antidepressant treatment for individuals who did not remit did not lead to superior outcomes, underscoring the need for further adaptive trials, treatment innovation, and an extended duration of care for relapse prevention. This sequential multiple assignment randomized trial evaluates the efficacy of an intervention strategy for individuals at ultrahigh risk of psychosis. Importance: Clinical trials have not established the optimal type, sequence, and duration of interventions for people at ultrahigh risk of psychosis. Objective: To determine the effectiveness of a sequential and adaptive intervention strategy for individuals at ultrahigh risk of psychosis. Design, Setting, and Participants: The Staged Treatment in Early Psychosis (STEP) sequential multiple assignment randomized trial took place within the clinical program at Orygen, Melbourne, Australia. Individuals aged 12 to 25 years who were seeking treatment and met criteria for ultrahigh risk of psychosis according to the Comprehensive Assessment of At-Risk Mental States were recruited between April 2016 and January 2019. Of 1343 individuals considered, 342 were recruited. Interventions: Step 1: 6 weeks of support and problem solving (SPS); step 2: 20 weeks of cognitive-behavioral case management (CBCM) vs SPS; and step 3: 26 weeks of CBCM with fluoxetine vs CBCM with placebo with an embedded fast-fail option of ω-3 fatty acids or low-dose antipsychotic medication. Individuals who did not remit progressed through these steps; those who remitted received SPS or monitoring for up to 12 months. Main Outcomes and Measures: Global Functioning: Social and Role scales (primary outcome), Brief Psychiatric Rating Scale, Scale for the Assessment of Negative Symptoms, Montgomery-Åsberg Depression Rating Scale, quality of life, transition to psychosis, and remission and relapse rates. Results: The sample comprised 342 participants (198 female; mean [SD] age, 17.7 [3.1] years). Remission rates, reflecting sustained symptomatic and functional improvement, were 8.5%, 10.3%, and 11.4% at steps 1, 2, and 3, respectively. A total of 27.2% met remission criteria at any step. Relapse rates among those who remitted did not significantly differ between SPS and monitoring (step 1: 65.1% vs 58.3%; step 2: 37.7% vs 47.5%). There was no significant difference in functioning, symptoms, and transition rates between SPS and CBCM and between CBCM with fluoxetine and CBCM with placebo. Twelve-month transition rates to psychosis were 13.5% (entire sample), 3.3% (those who ever remitted), and 17.4% (those with no remission). Conclusions and Relevance: In this sequential multiple assignment randomized trial, transition rates to psychosis were moderate, and remission rates were lower than expected, partly reflecting the ambitious criteria set and challenges with real-world treatment fidelity and adherence. While all groups showed mild to moderate functional and symptomatic improvement, this was typically short of remission. While further adaptive trials that address these challenges are needed, findings confirm substantial and sustained morbidity and reveal relatively poor responsiveness to existing treatments. Trial Registration: ClinicalTrials.gov Identifier: NCT02751632 [ABSTRACT FROM AUTHOR]

Objective: To develop targeted treatment for young people experiencing mental illness, a better understanding of the biological, psychological, and social changes is required, particularly during the early stages of illness. To do this, large datasets need to be collected using standardized methods. A harmonized data collection protocol was tested in a youth mental health research setting to determine its acceptability and feasibility. Method: Eighteen participants completed the harmonization protocol, including a clinical interview, self‐report measures, neurocognitive measures, and mock assessments of magnetic resonance imaging (MRI) and blood. The feasibility of the protocol was assessed by recording recruitment rates, study withdrawals, missing data, and protocol deviations. Subjective responses from participant surveys and focus groups were used to examine the acceptability of the protocol. Results: Twenty‐eight young people were approached, 18 consented, and four did not complete the study. Most participants reported positive subjective impressions of the protocol as a whole and showed interest in participating in the study again, if given the opportunity. Participants generally perceived the MRI and neurocognitive tasks as interesting and suggested that the assessment of clinical presentation could be shortened. Conclusion: Overall, the harmonized data collection protocol appeared to be feasible and generally well‐accepted by participants. With a majority of participants finding the assessment of clinical presentation too long and repetitive, the authors have made suggestions to shorten the self‐reports. The broader implementation of this protocol could allow researchers to create large datasets and better understand how psychopathological and neurobiological changes occur in young people with mental ill‐health. [ABSTRACT FROM AUTHOR]

Aim: Research has shown that preventative intervention in individuals at ultra‐high risk of psychosis (UHR) improves symptomatic and functional outcomes. The staged treatment in early psychosis (STEP) trial aims to determine the most effective type, timing and sequence of interventions in the UHR population by sequentially studying the effectiveness of (1) support and problem solving, (2) cognitive‐behavioural case management and (3) antidepressant medication with an embedded fast‐fail option of (4) omega‐3 fatty acids or low‐dose antipsychotic medication. This paper presents the recruitment flow and baseline clinical characteristics of the sample. Methods: STEP is a sequential multiple assignment randomized trial. We present the baseline demographics, clinical characteristics and acceptability and feasibility of this treatment approach as indicated by the flow of participants from first contact up until enrolment into the trial. Recruitment took place between April 2016 and January 2019. Results: Of 1343, help‐seeking young people who were considered for participation, 402 participants were not eligible and 599 declined/disengaged, resulting in a total of 342 participants enrolled in the study. The most common reason for exclusion was an active prescription of antidepressant medication. Eighty‐five percent of the enrolled sample had a non‐psychotic DSM‐5 diagnosis and symptomatic/functional measures showed a moderate level of clinical severity and functional impairment. Discussion: The present study demonstrates the acceptability and participant's general positive appraisal of sequential treatment. It also shows, in line with other trials in UHR individuals, a significant level of psychiatric morbidity and impairment, demonstrating the clear need for care in this group and that treatment is appropriate. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Introduction: Despite the established finding that migrants are at higher risk of developing a first-episode psychosis, they are under-represented in cohorts of young people identified as being at ultra-high risk for psychosis (UHR). Therefore, in order to determine the reasons for these conflicting findings, this study examined the pathways to care and clinical presentation of migrants attending an At-Risk Mental State clinic.Methodology: This study included consecutive UHR cases identified over five years attending the PACE clinic in Melbourne, Australia. The CAARMS was used to assess the severity of attenuated psychotic symptoms. Depressive symptoms and functioning were measured using the PHQ9 and GAF, respectively.Results: Over the five-year study period, 461 UHR young people attended the PACE clinic and 13.7% were first-generation migrants. A higher proportion of migrants were referred by community health services, such as general practitioners, than other referral sources. Australian born UHR patients were more likely to be referred via another mental health service. There was no difference in the type or severity of attenuated psychotic symptoms based on migrant status, except that there was a trend for young African migrants to have more severe unusual thought content. Depressive symptoms and poor functioning were highly prevalent across the total cohort and did not differ according to migrant status.Conclusions: It is not yet understood why migrants are under-represented in UHR cohorts. Qualitative interviews of migrants, who are not typically identified in the UHR stage, could provide insights into the barriers to accessing care. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Aim: To examine reasons for referral to a specialist ultra‐high risk (UHR) for psychosis clinic and whether these reasons are associated with risk for subsequent transition to psychosis. Methods: Data for 127 patients referred to the Personal Assessment and Crisis Evaluation clinic were collected by medical record audit. Time to transition to psychosis was calculated from date of referral to time at which the young person was judged by their treating team to be experiencing onset of first episode psychosis. Results: Patients were primarily referred due to attenuated psychotic symptoms and depression (40.2%). There was an association with transition, with those in the attenuated psychotic‐symptom‐only category being more likely to transition. Conclusion: As well as attenuated psychotic symptoms, depression and anxiety were also important reasons for referral indicating that there is a broad clinical phenotype of young people presenting to UHR clinics. Clinical reason for referral may index level of risk for subsequent transition to psychosis. [ABSTRACT FROM AUTHOR]

It is unclear whether there is a specific association between stressful experiences and obsessive-compulsive symptoms or whether this relationship is due to stressful experiences increasing risk for psychopathology generally. The current study examined the association between stressful experiences and obsessive-compulsive symptom dimensions, while adjusting for coexisting psychiatric symptoms and psychological distress in a young adult transdiagnostic at-risk sample. Forty-three participants completed self-report measures assessing obsessive-compulsive symptoms, stressful experiences, and a range of other psychiatric symptoms. Regression models examined the relationship between stressful experiences and different obsessive-compulsive symptoms dimensions (i.e., symmetry, fear of harm, contamination, and unacceptable thoughts), adjusting for the influence of coexisting psychiatric symptoms and psychological distress. The results showed that there was an association between stressful experiences and obsessive-compulsive symptoms dimension of symmetry. Symptoms of borderline personality disorder were positively associated with the obsessive-compulsive symptom dimensions of symmetry and fear of harm symptoms. Symptoms of psychosis were found to be negatively associated with the obsessive-compulsive symptoms dimension of fear of harm. These findings have implications for understanding the psychological mechanisms that underlie symmetry symptoms and highlight the need to study OCS dimensions separately to inform more precise, mechanism-targeted interventions. [ABSTRACT FROM AUTHOR]

• Docosahexaenoic acid plays an important role in ultra-high risk of psychosis status. • Fractional anisotropy significantly differed in ultra-high risk of psychosis remitters versus non-remitters. • Specific fatty acids showed a unique link to white matter integrity in ultra-high-risk individuals. Decreased white matter (WM) integrity and disturbance in fatty acid composition have been reported in individuals at ultra-high risk of psychosis (UHR). The current study is the first to investigate both WM integrity and erythrocyte membrane polyunsaturated fatty acid (PUFA) levels as potential risk biomarkers for persistent UHR status, and global functioning in UHR individuals. Forty UHR individuals were analysed at baseline for erythrocyte membrane PUFA concentrates. Tract-based spatial statistics (TBSS) was used to analyse fractional anisotropy (FA) and diffusivity measures. Measures of global functioning and psychiatric symptoms were evaluated at baseline and at 12-months. Fatty acids and WM indices did not predict functional outcomes at baseline or 12-months. Significant differences were found in FA between UHR remitters and non-remitters (individuals who no longer met UHR criteria versus those who continued to meet criteria at 12-months). Docosahexaenoic acid (DHA) was found to be a significant predictor of UHR status at 12-months, as was the interaction between the sum of ώ-3 and whole brain FA, and the interaction between the right anterior limb of the internal capsule and the sum of ώ-3. The results confirm that certain fatty acids have a unique relationship with WM integrity in UHR individuals. [ABSTRACT FROM AUTHOR]