Antipsychotic medication versus psychological intervention versus a combination of both in adolescents with first-episode psychosis (MAPS): a multicentre, three-arm, randomised controlled pilot and feasibility study

Background Evidence for the effectiveness of treatments in early-onset psychosis is sparse. Current guidance for the treatment of early-onset psychosis is mostly extrapolated from trials in adult populations. The UK National Institute for Health and Care Excellence has recommended evaluation of the clinical effectiveness and cost-effectiveness of antipsychotic drugs versus psychological intervention (cognitive behavioural therapy [CBT] and family intervention) versus the combination of these treatments for early-onset psychosis. The aim of this study was to establish the feasibility of a randomised controlled trial of antipsychotic monotherapy, psychological intervention monotherapy, and antipsychotics plus psychological intervention in adolescents with first-episode psychosis. Methods We did a multicentre pilot and feasibility trial according to a randomised, single-blind, three-arm, controlled design. We recruited participants from seven UK National Health Service Trust sites. Participants were aged 14–18 years; help-seeking; had presented with first-episode psychosis in the past year; were under the care of a psychiatrist; were showing current psychotic symptoms; and met ICD-10 criteria for schizophrenia, schizoaffective disorder, or delusional disorder, or met the entry criteria for an early intervention for psychosis service. Participants were assigned (1:1:1) to antipsychotics, psychological intervention (CBT with optional family intervention), or antipsychotics plus psychological intervention. Randomisation was via a web-based randomisation system, with permuted blocks of random size, stratified by centre and family contact. CBT incorporated up to 26 sessions over 6 months plus up to four booster sessions, and family intervention incorporated up to six sessions over 6 months. Choice and dose of antipsychotic were at the discretion of the treating consultant psychiatrist. Participants were followed up for a maximum of 12 months. The primary outcome was feasibility (ie, data on trial referral and recruitment, session attendance or medication adherence, retention, and treatment acceptability) and the proposed primary efficacy outcome was total score on the Positive and Negative Syndrome Scale (PANSS) at 6 months. Primary outcomes were analysed by intention to treat. Safety outcomes were reported according to as-treated status, for all patients who had received at least one session of CBT or family intervention, or at least one dose of antipsychotics. The study was prospectively registered with ISRCTN, ISRCTN80567433. Findings Of 101 patients referred to the study, 61 patients (mean age 16·3 years [SD 1·3]) were recruited from April 10, 2017, to Oct 31, 2018, 18 of whom were randomly assigned to psychological intervention, 22 to antipsychotics, and 21 to antipsychotics plus psychological intervention. The trial recruitment rate was 68% of our target sample size of 90 participants. The study had a low referral to recruitment ratio (around 2:1), a high rate of retention (51 [84%] participants retained at the 6-month primary endpoint), a high rate of adherence to psychological intervention (defined as six or more sessions of CBT; in 32 [82%] of 39 participants in the monotherapy and combined groups), and a moderate rate of adherence to antipsychotic medication (defined as at least 6 consecutive weeks of exposure to antipsychotics; in 28 [65%] of 43 participants in the monotherapy and combined groups). Mean scores for PANSS total at the 6-month primary endpoint were 68·6 (SD 17·3) for antipsychotic monotherapy (6·2 points lower than at randomisation), 59·8 (13·7) for psychological intervention (13·1 points lower than at randomisation), and 62·0 (15·9) for antipsychotics plus psychological intervention (13·9 points lower than at randomisation). A good clinical response at 6 months (defined as ≥50% improvement in PANSS total score) was achieved in four (22%) of 18 patients receiving antipsychotic monotherapy, five (31%) of 16 receiving psychological intervention, and five (29%) of 17 receiving antipsychotics plus psychological intervention. In as-treated groups, serious adverse events occurred in eight [35%] of 23 patients in the combined group, two [13%] of 15 in the antipsychotics group, four [24%] of 17 in the psychological intervention group, and four [80%] of five who did not receive any treatment. No serious adverse events were considered to be related to participation in the trial. Interpretation This trial is the first to show that a head-to-head clinical trial comparing psychological intervention, antipsychotics, and their combination is safe in young people with first-episode psychosis. However, the feasibility of a larger trial is unclear because of site-specific recruitment challenges, and amendments to trial design would be needed for an adequately powered clinical and cost-effectiveness trial that provides robust evidence

Role of the Arabidopsis PIN6 auxin transporter in auxin homeostasis and auxin-mediated development

Plant-specific PIN-formed (PIN) efflux transporters for the plant hormone auxin are required for tissue-specific directional auxin transport and cellular auxin homeostasis. The Arabidopsis PIN protein family has been shown to play important roles in developmental processes such as embryogenesis, organogenesis, vascular tissue differentiation, root meristem patterning and tropic growth. Here we analyzed roles of the less characterised Arabidopsis PIN6 auxin transporter. PIN6 is auxin-inducible and is expressed during multiple auxin–regulated developmental processes. Loss of pin6 function interfered with primary root growth and lateral root development. Misexpression of PIN6 affected auxin transport and interfered with auxin homeostasis in other growth processes such as shoot apical dominance, lateral root primordia development, adventitious root formation, root hair outgrowth and root waving. These changes in auxin-regulated growth correlated with a reduction in total auxin transport as well as with an altered activity of DR5-GUS auxin response reporter. Overall, the data indicate that PIN6 regulates auxin homeostasis during plant development.Christopher I. Cazzonelli, Marleen Vanstraelen, Sibu Simon, Kuide Yin, Ashley Carron-Arthur, Nazia Nisar, Gauri Tarle, Abby J. Cuttriss¤, Iain R. Searle, Eva Benkova, Ulrike Mathesius, Josette Masle, Jiří Friml, Barry J. Pogso

A three-arm feasibility randomised controlled trial comparing antipsychotic medication to psychological intervention to a combined treatment in adolescents with first episode psychosis: The Managing Adolescent first episode Psychosis Study (MAPS)

Background: The evidence base for treatments for early-onset psychosis (EOP) is limited and of low quality. Current guidance for the treatment of EOP is mostly extrapolated from trials in adult populations. NICE, in the United Kingdom (UK), make a specific research recommendation for the evaluation of clinical and cost-effectiveness of antipsychotics (AP), versus psychological intervention (cognitive behaviour therapy [CBT] and family intervention), versus combination treatment for EOP. The National Institute for Health Research (NIHR) in the UK commissioned this research to establish feasibility and acceptability of a definitive trial examining these three treatment options. Methods: We conducted a multi-site, Prospective Randomised Open Blinded Evaluation (PROBE) design, feasibility randomised controlled trial (RCT) comparing AP monotherapy with psychological intervention monotherapy (PI) plus a combination of these treatments in 14-18-year olds with a first episode of psychosis. We recruited participants from seven United Kingdom sites. Participants were followed-up at six and 12 months. Cognitive behavioural therapy incorporated up to 26 sessions over 6 months plus up to four booster sessions. Family intervention included up to six sessions over 6 months. Choice and dose of antipsychotic were at the discretion of the treating consultant psychiatrist. The primary outcome was feasibility data (recruitment, retention, acceptability) and the main effectiveness outcome was the Positive and Negative Syndrome Scale (PANSS) total score at 6 months. We conducted a repeated-measures analysis of the proposed primary outcome (PANSS) and the secondary outcome, the Questionnaire about the Process of Recovery (QPR) using a mixed effects model to account for the discrete timing of the follow-up assessments and adjusted for site. Safety outcomes were reported on the basis of as treated status defined as any one session of CBT or any one dose of APs; descriptive statistics are reported for safety outcomes. The study was prospectively registered on 27th February 2017, http://www.isrctn.com/ISRCTN80567433. Findings: 61 patients (aged 14-18 years; mean 16.3, SD 1.3) were recruited from 1st April 2017 to 31st October 2018, 18 were assigned to psychological intervention, 22 to antipsychotics and 21 to the combination. The feasibility of recruitment was unclear, since the trial only recruited 61 of a target of 90 participants. The study had a low referral: randomisation ratio (101:61), high rates of retention (>80%), high rates of adherence for psychological intervention (82.1%) defined as 6 or more sessions of CBT, and moderate rates of adherence for antipsychotic medication (65.1%), defined as 6 or more consecutive weeks of APs. The median number of sessions for CBT for those in the PI arm was 14 (IQR 9, 23) and 15 in the combined arm (IQR 9, 17). Of those in receipt of APs the mean duration that the participant remained on the medication was 31.5 weeks (SD 14.6, minimum 8.7 and maximum 52). There were no serious adverse events considered to be related to the trial. Interpretation: This is the first trial to show that it is safe to conduct a head-to-head clinical trial comparing psychological intervention with antipsychotics and the combination in people in young people with a first-episode psychosis. However, feasibility is unclear due to not meeting the recruitment progression criteria, so amendments to trial design are required in order to conduct an adequately powered clinical and cost effectiveness trial to provide robust evidence

Timing and nature of fluid flow and alteration during Mesoproterozoic shear zone formation, Olary Domain, South Australia

The definitive version is available at www.blackwell-synergy.comThe development of shear zones at mid-crustal levels in the Proterozoic Willyama Supergroup was synchronous with widespread fluid flow resulting in albitization and calcsilicate alteration. Monazite dating of shear zone fabrics reveal that they formed at 1582 ± 22 Ma, at the end of the Olarian D3 deformational event and immediately prior to the emplacement of regional S-type granites. Two stages of fluid flow are identified in the area: first an albitizing event which involved the addition of Na and loss of Si, K and Fe; and a second phase of calcsilicate alteration with additions of Ca, Fe, Mg and Si and removal of Na. Fluid fluxes calculated for albitization and calcsilicate alteration were 5.56 x 109 to 1.02 x 1010 mol m-2 and 2.57 x 108–5.20 x 109 mol m-2 respectively. These fluxes are consistent with estimates for fluid flow through mid-crustal shear zones in other terranes. The fluids associated with shearing and alteration are calculated to have d18O and dD values ranging between +8 and +11%, and -33 and -42%, respectively, and eNd values between -2.24 and -8.11. Our results indicate that fluids were derived from metamorphic dehydration of the Willyama Supergroup metasediments. Fluid generation occurred during prograde metamorphism of deeper crustal rocks at or near peak pressure conditions. Shear zones acted as conduits for major crustal fluid flow to shallow levels where peak metamorphic conditions had been attained earlier leading to the apparent ‘retrograde’ fluid-flow event. Thus, the peak metamorphism conditions at upper and lower crustal levels were achieved at differing times, prior to regional granite formation, during the same orogenic cycle leading to the formation of retrograde mineral assemblages during shearing.C. Clark, A. Schmidt Mumm, K. Faur

Up-temperature flow of surface-derived fluids in the mid-crust: the role of pre-orogenic burial of hydrated fault rocks

The definitive version is available at www.blackwell-synergy.comThe Walter-Outalpa shear zone in the southern Curnamona Province of NE South Australia is an example of a shear zone that has undergone intensely focused fluid flow and alteration at mid-crustal depths. Results from this study have demonstrated that the intense deformation and ductile shear zone reactivation, at amphibolite facies conditions of 534 ± 20 °C and 500 ± 82 MPa, that overprint the Proterozoic Willyama Supergroup occurred during the Delamerian Orogeny (c. 500 Ma) (EPMA monazite ages of 501 ± 16 and 491 ± 19 Ma). This is in contrast to the general belief that the majority of basement deformation and alteration in the southern Curnamona Province occurred during the waning stages of the Olarian Orogeny (c. 1610–1580 Ma). These shear zones contain hydrous mineral assemblages that cut wall rocks that have experienced amphibolite facies metamorphism during the Olarian Orogeny. The shear zone rock volumes have much lower d18O values (as low as 1&) than their unsheared counterparts (7–9%), and calculated fluid d18O values (5–8%) consistent with a surfacederived fluid source. Hydrous minerals show a decrease in dD(H2O) from -14 to -22%, for minerals outside the shear zones, to -28 to -40%, for minerals within the shear zones consistent with a contribution from a meteoric source. It is unclear how near-surface fluids initially under hydrostatic pressure penetrate into the middle crust where fluid pressures approach lithostatic, and where fluid flow is expected to be dominantly upward because of pressure gradients. We propose a mechanism whereby faulting during basin formation associated with the Adelaidean Rift Complex (c. 700 Ma) created broad hydrous zones containing mineral assemblages in equilibrium with surface waters. These panels of fault rock were subsequently buried to depths where the onset of metamorphism begins to dehydrate the fault rock volumes evolving a low d18O fluid that is channelled through shear zones related to Delamerian Orogenic activity.C. Clark, M. Hand, K. Faure and A. Schmidt Mum