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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.

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., (© 2022 John Wiley & Sons Australia, Ltd.)

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., (© 2018 John Wiley & Sons Australia, Ltd.)

Aim: It is now necessary to investigate whether recovery in psychosis is possible without the use of antipsychotic medication. This study will determine (1) whether a first-episode psychosis (FEP) group receiving intensive psychosocial interventions alone can achieve symptomatic remission and functional recovery; (2) whether prolonging the duration of untreated psychosis (DUP) in a sub-group according to randomisation will be associated with a poorer outcome and thereby establish whether the relationship between DUP and outcome is causative; and (3) whether neurobiological changes observed in FEP are associated with the psychotic disorder or antipsychotic medication. Baseline characteristics of participants will be presented., Methods: This study is a triple-blind randomized placebo-controlled non-inferiority trial. The primary outcome is the level of functioning measured by the Social and Occupational Functioning Assessment Scale at 6 months. This study is being conducted at the Early Psychosis Prevention and Intervention Centre, Melbourne and includes young people aged 15 to 24 years with a DSM-IV psychotic disorder, a DUP less than 6 months and not high risk for suicide or harm to others. Strict discontinuation criteria are being applied. Participants are also undergoing three 3-Tesla-MRI scans., Results: Ninety participants have been recruited and baseline characteristics are presented., Conclusions: Staged treatment and acceptability guidelines in early psychosis will determine whether antipsychotic medications are indicated in all young people with a FEP and whether antipsychotic medication can be safely delayed. Furthermore, the relative contribution of psychotic illness and antipsychotic medication in terms of structural brain changes will also be elucidated. The findings will inform clinical practice guidelines., (© 2018 John Wiley & Sons Australia, Ltd.)

Risperidone is metabolized by polymorphic enzymes, and a large variability in plasma concentration and therapeutic response is observed. Risperidone long-acting injection (RLAI) avoids the first-pass effect, and little is known about the influence of gene polymorphisms involved in its pharmacokinetics. The influence on plasma concentrations of risperidone (RIS), its metabolite 9-hydroxy-risperidone, and on adverse effects were investigated for polymorphisms of cytochrome P450 2D6 (CYP2D6) (*3, *4, *5, *6), CYP3A (CYP3A4*1B, CYP3A4 rs4646437, CYP3A5*3, CYP3A7*1C), ABCB1 (1236C>T, 2677G>T, 3435C>T), NR1/2 coding for pregnane X receptor (rs1523130, rs2472677, rs7643645), and for CYP3A activity measured by a phenotyping test. Forty-two patients with at least 4 consecutive unchanged doses of RLAI were included in a multicenter cross-sectional study. A 55% lower dose-adjusted plasma levels of RIS were observed for CYP2D6 ultrarapid metabolizers (n = 5) as compared with CYP2D6 intermediate metabolizers (P < 0.007). NR1/2 polymorphism (rs7643645A>G) influenced RIS exposure with a 2.8-fold lower active moiety (P = 0.031) in GG compared with the AA genotype. This was confirmed in a second independent cohort (n = 16). Furthermore, high-density lipoprotein cholesterol was positively correlated with CYP3A activity (P = 0.01), and the NR1/2 (rs2472677) polymorphism was associated with different adverse effects including prolactin plasma levels adjusted for age and sex. In conclusion, our results confirmed the influence of CYP2D6 genotype on plasma levels of RIS. This is the first report on the influence of NR1/2 polymorphisms on RLAI exposure and on drug-induced adverse effects. These results should be validated in larger cohorts.

Aim: Duration of untreated psychosis (DUP) refers to the time elapsing between psychosis onset and treatment initiation. Despite a certain degree of consensus regarding the definition of psychosis onset, the definition of treatment commencement varies greatly between studies and DUP may be underestimated due to lack of agreement. In the present study, three sets of criteria to define the end of the untreated period were applied in a first-episode psychosis cohort to assess the impact of the choice of definition on DUP estimation., Methods: The DUP of 117 patients admitted in the Treatment and Early Intervention in Psychosis Program Psychosis in Lausanne was measured using the following sets of criteria to define treatment onset: (i) initiation of antipsychotic medication; (ii) entry into a specialized programme; and (iii) entry into a specialized programme and adequate medication with a good compliance., Results: DUP varied greatly according to definitions, the most restrictive criteria leading to the longest DUP (median DUP1=2.2 months, DUP2=7.4 months and DUP3=13.6 months). A percentage of 19.7 of the patients who did not meet these restrictive criteria had poorer premorbid functioning and were more likely to use cannabis. Longer DUP3 was associated with poorer premorbid functioning and with younger age at onset of psychosis., Conclusion: These results underline the need for a unique and standardized definition of the end of DUP. We suggest that the most restrictive definition of treatment should be used when using the DUP concept in future research., (© 2011 Blackwell Publishing Asia Pty Ltd.)

Objective: To assess dosing, efficacy, and tolerability of quetiapine fumarate in drug-naive first-episode psychosis., Method: We present a prospective, randomized, controlled, single-center, double-blind, fixed-dose, 4-week comparison study of 200 mg/day versus 400 mg/day of quetiapine in 141 drug-naive acutely ill first-episode psychosis patients (diagnosed according to DSM-IV) aged 15 to 25 years. The double-blind 4-week trial (Part 1) was followed by a single-blind, naturalistic, flexible-dose 8-week period (Part 2). The main outcome measures were symptomatic change, functioning, and tolerability. Data were collected from July 2003 until January 2006., Results: The estimated time trends of the linear mixed-effects modeling indicated that efficacy between the 2 treatment groups in Part 1 was similar for most outcome measures except for 5 measures: the Scale for the Assessment of Negative Symptoms (SANS) anhedonia-asociality subscale (p = .011), the Social and Occupational Functioning Assessment Scale (p = .020), the Global Assessment of Functioning scale (p = .070), the SANS affective flattening or blunting subscale (p = .051), and the Udvalg for Kliniske Undersogelser total (p = .056), suggesting that the 200-mg group improved more for the SANS anhedonia-asociality subscale, whereas the 400-mg group showed a slight deterioration. Social and global functioning also improved more in the 200-mg group than in the 400-mg group. Part 2 of the study revealed that, independent of the initial target dose, when clinicians were able to adjust the dose flexibly, the dose at 12 weeks was similar between groups and averaged 268 mg/day., Conclusion: Our study in acutely ill drug-naive first-episode psychosis patients suggests that quetiapine is a safe and well-tolerated antipsychotic medication. In contrast to multiepisode patients, dosing should be more conservative in untreated new-onset cases. An initial dose of 250 to 300 mg/day of quetiapine is proposed as a primary target dose in drug-naive first-episode psychosis patients., Trial Registration: clinicaltrials.gov Identifier: NCT00449397., (Copyright 2008 Physicians Postgraduate Press, Inc.)

This study examined whether distress in relation to attenuated psychotic symptoms (DAPS) is associated with clinical outcomes in an ultra-high risk (UHR) for psychosis sample. We also investigated whether DAPS is associated with cognitive style (attributional style and cognitive biases) and whether amount of psychosocial treatment provided is associated with reduction in DAPS. The study was a secondary analysis of the "Neurapro" clinical trial of omega-3 fatty acids. Three hundred and four UHR patients were recruited across 10 early intervention services. Data from baseline assessment, regular assessments over 12 months, and medium term follow-up (mean = 3.4 years) were used for analysis. Findings indicated: a positive association between DAPS assessed over time and transition to psychosis; a significant positive association between baseline and longitudinal DAPS and transdiagnostic clinical and functional outcomes; a significant positive association between baseline and longitudinal DAPS and nonremission of UHR status. There was no relationship between severity of DAPS and cognitive style. A greater amount of psychosocial treatment (cognitive-behavioral case management) was associated with an increase in DAPS scores. The study indicates that UHR patients who are more distressed by their attenuated psychotic symptoms are more likely to have a poorer clinical trajectory transdiagnostically. Assessment of DAPS may therefore function as a useful marker of risk for a range of poor outcomes. The findings underline the value of repeated assessment of variables and incorporation of dynamic change into predictive modeling. More research is required into mechanisms driving distress associated with symptoms and the possible bidirectional relationship between symptom severity and associated distress. [ABSTRACT FROM AUTHOR]

Aim The 'ultra-high-risk' criteria identify a clinical population at substantially increased risk for progressing to schizophrenia and other psychotic disorders. Although a number of clinical variables predictive of transition to psychotic disorder have been identified within this population, the predictive value of the level of distress associated with attenuated psychotic symptoms has not yet been examined. This was the aim of the present study. Method The level of distress (0-100) associated with attenuated psychotic symptoms was recorded for 70 ultra-high-risk ( UHR) patients using the Comprehensive Assessment of At-Risk Mental State ( CAARMS). Transition to psychosis was assessed over a 16-month follow-up period. Results Of the 70 UHR patients, 15 transitioned to psychosis (21.4%). Of the four CAARMS subscales measuring attenuated positive symptoms, Perceptual Abnormalities was rated as the most distressing. There were no differences in CAARMS scales rated as the most distressing between those who transitioned to psychosis and those who did not. There was also no association between higher levels of distress associated with attenuated psychotic symptoms and transition to psychosis. Conclusion Although the findings require replication, they indicate that the degree of distress associated with attenuated psychotic symptoms should not be used as a criterion for enriching UHR samples for risk of frank psychotic disorder. [ABSTRACT FROM AUTHOR]

Background While reduction of DUP (Duration of Untreated Psychosis) is a key goal in early intervention strategies, the predictive value of DUP on outcome has been questioned. We planned this study in order to explore the impact of three different definition of “treatment initiation” on the predictive value of DUP on outcome in an early psychosis sample. Methods 221 early psychosis patients aged 18–35 were followed-up prospectively over 36 months. DUP was measured using three definitions for treatment onset: Initiation of antipsychotic medication (DUP1); engagement in a specialized programme (DUP2) and combination of engagement in a specialized programme and adherence to medication (DUP3). Results 10% of patients never reached criteria for DUP3 and therefore were never adequately treated over the 36-month period of care. While DUP1 and DUP2 had a limited predictive value on outcome, DUP3, based on a more restrictive definition for treatment onset, was a better predictor of positive and negative symptoms, as well as functional outcome at 12, 24 and 36 months. Globally, DUP3 explained 2 to 5 times more of the variance than DUP1 and DUP2, with effect sizes falling in the medium range according to Cohen. Conclusions The limited predictive value of DUP on outcome in previous studies may be linked to problems of definitions that do not take adherence to treatment into account. While they need replication, our results suggest effort to reduce DUP should continue and aim both at early detection and development of engagement strategies. [ABSTRACT FROM AUTHOR]