Isolating the impact of antipsychotic medication on metabolic health: Secondary analysis of a randomized controlled trial of antipsychotic medication versus placebo in antipsychotic medication naïve first-episode psychosis (the STAGES study).

BACKGROUND: Cardiovascular and metabolic diseases are the leading contributors to the early mortality associated with psychotic disorders. To date, it has not been possible to disentangle the effect of medication and non-medication factors on the physical health of people with a first episode of psychosis (FEP). This study aimed to isolate the effects of antipsychotic medication on anthropometric measurements, fasting glucose and lipids. METHODS: This study utilized data from a triple-blind randomized placebo-controlled trial comparing two groups of antipsychotic-naïve young people with a FEP who were randomized to receive a second-generation antipsychotic medication (FEP-medication group) or placebo (FEP-placebo group) for 6 months. Twenty-seven control participants were also recruited. RESULTS: Eighty-one participants commenced the trial; 69.1% completed at least 3 months of the intervention and 33.3% completed the full 6 months. The FEP-placebo group gained a mean of 2.4 kg (±4.9) compared to 1.1 kg (±4.9) in the control participants (t = 0.76, p = .45). After controlling for multiple analyses, there was no difference in blood pressure, waist circumference or heart rate between the FEP-placebo group and controls. After 6 months, the FEP medication group had gained 4.1 kg (±4.5), higher than those receiving placebo but not statistically significant (t = 0.8, p = .44). There were no differences in fasting glucose or lipids between the FEP groups after 3 months. CONCLUSIONS: While limited by small numbers and high attrition, these findings indicate that some of the metabolic complications observed in psychotic disorders could be attributable to factors other than medication. This emphasizes the need to deliver physical health interventions early in the course of FEP.

Leveraging the social network for treatment of social anxiety: Pilot study of a youth-specific digital intervention with a focus on engagement of young men.

OBJECTIVE: The primary objective was to determine the acceptability, feasibility and safety of a novel digital intervention (Entourage) for young people with prominent social anxiety symptoms, with a particular focus on the engagement of young men. The secondary aim was to explore whether the intervention was associated with clinically significant improvements to clinical and social variables known to co-occur with social anxiety. METHOD: A multidisciplinary team comprising of mental health clinicians, researchers, young adult fiction writers, a comic artist and young people with a lived experience of social anxiety developed the Entourage platform in collaboration. Entourage combines evidence-based therapeutic techniques for social anxiety with an engaging, social-media-based interface that allows users to build social connections, while also receiving expert clinical moderation and support from peer workers. Acceptability, feasibility and safety outcomes of Entourage were tested in a 12-week pilot study with 89 young people (48.3% male; age M = 19.8 years, SD = 3.3 years). Eligible participants were recruited via liaison with four headspace early-intervention centres in north-western Melbourne. RESULTS: 56.8% of the sample reported social anxiety symptoms in the severe or very severe range at baseline. Results demonstrated the Entourage intervention was feasible, safe, and potentially acceptable, with 98.6% of participants reporting they would recommend Entourage to another young person experiencing social anxiety. Usage results were also comparable across male and non-male participants. Results showed that young people reliably and significantly improved on clinical and social variables. In particular, young males showed a clinically significant improvement on social anxiety symptoms (d = 0.79, p < .001), depression (d = 0.71, p < .001), belongingness (d = 0.58, p = .001), increased feelings of social connectedness (d = 0.46, p = .004) and decreased loneliness (d = 0.46, p = .006). Non-male participants also experienced a significant increase in social connectedness (d = 0.76, p < .001), alongside reduced social anxiety (d = 0.78, p < .001) and experiential avoidance (d = 0.81, p < .001). CONCLUSIONS: Entourage is a highly engaging and potentially effective intervention that represents a novel combination of features designed both to reduce social anxiety symptoms and improve social connection among young people. Entourage demonstrated some acceptability, feasibility and safety, with encouraging benefits to clinical and social variables. Entourage also showed favorable results for the engagement and support of young men with social anxiety symptoms.

Youth Depression Alleviation with Anti-inflammatory Agents (YoDA-A): a randomised clinical trial of rosuvastatin and aspirin.

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.

The addition of fluoxetine to cognitive behavioural therapy for youth depression (YoDA-C): a randomised, double-blind, placebo-controlled, multicentre clinical trial.

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-Åsberg 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.

Youth Depression Alleviation-Augmentation with an anti-inflammatory agent (YoDA-A): protocol and rationale for a placebo-controlled randomized trial of rosuvastatin and aspirin.

AIM: There is growing support for the role of inflammation and oxidative stress in the pathophysiology of major depressive disorder (MDD). This has led to the development of novel strategies targeting inflammation in the treatment of depression. Rosuvastatin and aspirin have well-documented, anti-inflammatory and antioxidant properties. The aim of the Youth Depression Alleviation: Augmentation with an anti-inflammatory agent (YoDA-A) study is to determine whether individuals receiving adjunctive anti-inflammatory agents, aspirin and rosuvastatin experience a reduction in the severity of MDD compared with individuals receiving placebo. METHODS: YoDA-A is a 12-week triple-blind, randomized controlled trial funded by the National Health and Medical Research Council, Australia. Participants aged 15-25, with moderate-to-severe MDD, are allocated to receive either 10 mg/day rosuvastatin, 100 mg/day aspirin, or placebo, in addition to treatment as usual. Participants are assessed at baseline and at weeks 4, 8, 12 and 26. The primary outcome is change in the Montgomery-Åsberg Depression Rating Scale (MADRS) from baseline to week 12. RESULTS: The study is planned to be completed in 2017. At date of publication, 85 participants have been recruited. CONCLUSION: Timely and targeted intervention for youth MDD is crucial. Given the paucity of new agents to treat youth MDD, adjunctive trials are not only pragmatic and 'real-world', but additionally aim to target shortfalls in conventional medications. This study has the potential to first provide two new adjunctive treatment options for youth MDD; aspirin and rosuvastatin. Second, this study will serve as proof of principle of the role of inflammation in MDD.

Evidence-based knowledge in the context of social practice.

AIMS: Social practitioners require evidence-based knowledge as a guide to the development of social policies and practices. This article aims to identify: (1) knowledge domains needed for the development and use of evidence-based knowledge in social practice; (2) promising research methods for such knowledge development; (3) a framework for linking evidence-based practice, systematic reviews, and practice guidelines, as well as standards for systematic reviews and guidelines; (4) issues influencing use of evidence-based knowledge in social practice. METHODS: This analysis is based on examination of conceptualisations of social practice in a transdisciplinary, evidence-based practice context. Also examined are recent national level reports pertaining to comparative effectiveness research. RESULTS: This review identifies key knowledge domains pertinent to a transdisciplinary systems conceptualisation of evidence-based practice and promising comparative effectiveness research methods pertaining to those domains. An integrative conceptualisation of evidence-based practice is proposed including linkages to systematic reviews and practice guidelines. CONCLUSIONS: The development of evidence-based knowledge for social practice can benefit from the use of comparative effectiveness research strategies using a range of research methods tailored to specific questions and resource requirements, and which examine effectiveness and cost-effectiveness. An integrating conceptualisation of evidence-based practice that includes a linked process including planned and targeted systematic reviews and guideline development for decision making is needed to facilitate knowledge development and use. Evidence-based research regarding social intervention outcomes can benefit by using conceptual models that view intervention effects as contingent on sets of interacting domains including environmental, organisational, intervener, client-system, technology, and technique variables.

Implementing evidence-based practice: practitioner assessment of an agency-based training program.

Responding to the call for evidence-based practice (EBP) in social work, the authors conducted a multiphase exploratory study to test the acceptability of a training-based collaborative agency-university partnership strategy supporting EBP. The Bringing Evidence for Social Work Training (BEST) study includes an agency training component consisting of 10 modules designed to support the implementation of EBP in social agencies. Qualitative data from post-training participant focus groups were analyzed in order to describe practitioner perceptions of the 10 training modules and trainer experiences of implementation. Based on the findings from this study the authors suggest that the BEST training was generally acceptable to agency team members, but not sufficient to sustain the use of EBP in practice.

Toward a transdisciplinary model of evidence-based practice.

CONTEXT: This article describes the historical context and current developments in evidence-based practice (EBP) for medicine, nursing, psychology, social work, and public health, as well as the evolution of the seminal "three circles" model of evidence-based medicine, highlighting changes in EBP content, processes, and philosophies across disciplines. METHODS: The core issues and challenges in EBP are identified by comparing and contrasting EBP models across various health disciplines. Then a unified, transdisciplinary EBP model is presented, drawing on the strengths and compensating for the weaknesses of each discipline. FINDINGS: Common challenges across disciplines include (1) how "evidence" should be defined and comparatively weighted; (2) how and when the patient's and/or other contextual factors should enter the clinical decision-making process; (3) the definition and role of the "expert"; and (4) what other variables should be considered when selecting an evidence-based practice, such as age, social class, community resources, and local expertise. CONCLUSIONS: A unified, transdisciplinary EBP model would address historical shortcomings by redefining the contents of each model circle, clarifying the practitioner's expertise and competencies, emphasizing shared decision making, and adding both environmental and organizational contexts. Implications for academia, practice, and policy also are discussed.

12-year outcomes following permanent prostate brachytherapy in patients with clinically localized prostate cancer.

PURPOSE: We reviewed the outcomes in men treated with permanent prostate brachytherapy (PPB). MATERIAL AND METHODS: A total of 1,449 consecutive patients with a mean age of 68 years treated with PPB between 1992 and 2000 and mean pretreatment prostate specific antigen (PSA) 10.1 ng/ml were included in this study. Of the patients 55% presented with Gleason 6 tumors and 28% had Gleason 7 disease. A total of 400 patients (27%) were treated with neoadjuvant hormones and 301 (20%) were treated in combination with external radiation plus PPB. Several biochemical freedom from recurrence (BFR) definitions were determined. Statistical analysis consisted of log rank testing, Kaplan-Meier estimates and Cox regression analysis. RESULTS: Median followup was 82 months with 39 patients at risk at for 144 months. Overall and disease specific survival at 12 years was 81% and 93%, respectively. The 12-year BFR was 81%, 78%, 74% and 77% according to the American Society for Therapeutic Radiology and Oncology (ASTRO), ASTRO-Kattan, ASTRO-Last Call and Houston definitions, respectively. The 12-year ASTRO-Kattan BFR using risk stratification was 89%, 78% and 63% in patients at low, intermediate and high risk, respectively (p = 0.0001). Multivariate analysis identified the dose that 90% of the target volume received (p <0.0001), pretreatment PSA (p = 0.001), Gleason score (p = 0.002), the percent positive core biopsies (p = 0.037), clinical stage (p = 0.689), the addition of hormones (p = 0.655) and the addition of external radiation (p = 0.724) for predicting BFR-ASTRO. Five-year disease specific survival was 44% in patients with a PSA doubling time of less than 12 months vs 88% in those with a PSA doubling time of 12 months or greater (p = 0.0001). CONCLUSIONS: PPB offers acceptable 12-year BFR in patients who present with clinically localized prostate cancer. Implant dosimetry continues as an important predictor for BFR, while the addition of adjuvant therapies such as hormones and external radiation are insignificant. In patients who experience biochemical failure it appears that PSA doubling time is an important predictor of survival.

12-year outcomes following permanent prostate brachytherapy in patients with clinically localized prostate cancer.

PURPOSE: We reviewed the outcomes in men treated with permanent prostate brachytherapy (PPB). MATERIAL AND METHODS: A total of 1,449 consecutive patients with a mean age of 68 years treated with PPB between 1992 and 2000 and mean pretreatment prostate specific antigen (PSA) 10.1 ng/ml were included in this study. Of the patients 55% presented with Gleason 6 tumors and 28% had Gleason 7 disease. A total of 400 patients (27%) were treated with neoadjuvant hormones and 301 (20%) were treated in combination with external radiation plus PPB. Several biochemical freedom from recurrence (BFR) definitions were determined. Statistical analysis consisted of log rank testing, Kaplan-Meier estimates and Cox regression analysis. RESULTS: Median followup was 82 months with 39 patients at risk at for 144 months. Overall and disease specific survival at 12 years was 81% and 93%, respectively. The 12-year BFR was 81%, 78%, 74% and 77% according to the American Society for Therapeutic Radiology and Oncology (ASTRO), ASTRO-Kattan, ASTRO-Last Call and Houston definitions, respectively. The 12-year ASTRO-Kattan BFR using risk stratification was 89%, 78% and 63% in patients at low, intermediate and high risk, respectively (p = 0.0001). Multivariate analysis identified the dose that 90% of the target volume received (p <0.0001), pretreatment PSA (p = 0.001), Gleason score (p = 0.002), the percent positive core biopsies (p = 0.037), clinical stage (p = 0.689), the addition of hormones (p = 0.655) and the addition of external radiation (p = 0.724) for predicting BFR-ASTRO. Five-year disease specific survival was 44% in patients with a PSA doubling time of less than 12 months vs 88% in those with a PSA doubling time of 12 months or greater (p = 0.0001). CONCLUSIONS: PPB offers acceptable 12-year BFR in patients who present with clinically localized prostate cancer. Implant dosimetry continues as an important predictor for BFR, while the addition of adjuvant therapies such as hormones and external radiation are insignificant. In patients who experience biochemical failure it appears that PSA doubling time is an important predictor of survival.