Real-life effectiveness of transitioning from paliperidone palmitate 1-monthly to paliperidone palmitate 3-monthly long-acting injectable formulation.

Background: Non-adherence to antipsychotics in schizophrenia is associated with an increased risk of psychotic relapse and hospitalization, a risk that is reduced with the use of long-acting injectable (LAI) antipsychotics. Randomized clinical trials (RCTs) have demonstrated the efficacy of paliperidone palmitate 3-monthly (PP3M) for psychotic relapse prevention in schizophrenia, but it remains poorly documented among individuals treated in real-life settings who can benefit the most out of LAIs. Objectives: The objective of this study was to evaluate the effectiveness of PP3M in relapse prevention among patients with schizophrenia. Methods: This is a multicentre retrospective study conducted in four outpatients' clinics across Canada. All consecutive patients with a main diagnosis of schizophrenia who initiated PP3M between June 2016 and March 2020 were included. The primary outcome was psychotic relapse, defined using broad and clinically relevant criteria. Results: Among 178 consecutive patients who were switched to PP3M, the 12-month relapse rate was 18.5% and the relapse-free survival probability was 0.788 (95% confidence interval [CI] = 0.725-0.856). Comorbid diagnoses of personality disorders and substance use disorders were associated with hazard rates (HRs) of 3.6 (95% CI = 1.8-7.3, p < 0.001) and 3.1 (95% CI = 1.6-6.2), respectively. Increased psychopathology severity was associated with an increased likelihood of relapse, while having a job or being in school was protective. Conclusion: These findings reinforce the necessity of conducting research in patients with comorbid psychiatric disorders who are typically underrepresented in RCTs, yet overrepresented in real-life settings, in order to better inform and guide clinical practice.

Young Adults' Perspectives on Factors Related to Relapse After First-Episode Psychosis: Qualitative Focus Group Study.

Relapse after first-episode psychosis (FEP) is a major clinical challenge for specialized early intervention services. Understanding patient perspectives on factors contributing to relapse can inform the development of risk assessments and preventive interventions. The objective of this study was to identify factors that may contribute to and prevent relapse from the perspectives of patients receiving services for FEP. Data from 25 participants across four focus groups in Canada were analyzed with a descriptive content analysis approach. Twelve factors were identified, of which four (social environment, technology use, medication, and lifestyle behaviors) had both contributory and preventive roles. In descending order of frequency, risk factors for relapse included substance use; unsupportive social environment; technology use; taking and not taking medication; lack of sleep; work, career, or school stress; significant life events; symptoms of depression or mania; generalized worry; and financial stress. Preventive factors consisted of having a supportive social environment, using technology, taking medication, using coping strategies, and engaging in healthy lifestyle behaviors and meaningful activities. These findings extend the literature on relapse vulnerability and protective factors. Importantly, the factors identified in this study are modifiable, and thereby provide insights for the development and optimization of relapse risk assessments and preventive interventions.

Randomized, Placebo-Controlled Effectiveness Study of Quetiapine XR in Comorbid Depressive and Anxiety Disorders.

Objective: Quetiapine is approved as an adjunctive treatment for major depressive disorder (MDD) and as monotherapy for bipolar depression. It is often used off-label for treating anxiety conditions and as an augmentation agent for treatment-resistant depression. However, its benefit in depression with comorbid anxiety disorders has not been systematically evaluated. The current study evaluated the benefit and tolerability of quetiapine as augmentation to first-line antidepressants for MDD comorbid with anxiety disorders.Methods: In this multicenter trial (June 2008-June 2013), 76 adults (aged 18-65 years) with a primary diagnosis of unipolar depression comorbid with at least 1 anxiety disorder (per DSM-IV-TR criteria) received flexible-dose quetiapine extended-release (XR) 50-300 mg/d or placebo as add-on for 12 weeks in a 2:1 ratio. Depression, anxiety, life satisfaction, and adverse events were assessed.Results: Depression, anxiety, and function improved significantly in both groups. On primary outcome measures, quetiapine was superior to placebo in improving depression (17-item Hamilton Depression Rating Scale score: mean difference = -3.64; 95% CI, -7.01 to -0.27) and anxiety symptoms (Hamilton Anxiety Rating Scale score: mean difference = -4.02; 95% CI, -7.41 to -0.64), as well as Clinical Global Impressions-Severity of Illness scale score (mean difference = -0.64; 95% CI, -1.13 to -0.15). On secondary measures including the Montgomery-Asberg Depression Rating Scale, Beck Depression Inventory, Penn State Worry Questionnaire, and Quality of Life Satisfaction and Enjoyment Questionnaire, quetiapine produced a greater degree of improvement compared to placebo, but group differences were not statistically significant. Quetiapine was well tolerated, with mostly minor and no serious adverse effects.Conclusions: Quetiapine augmentation may be a useful intervention for MDD with comorbid anxiety.Trial Registration: ClinicalTrials.gov Identifier: NCT00688818.

Clinical utility of combinatorial pharmacogenomic testing in depression: A Canadian patient- and rater-blinded, randomized, controlled trial.

The pharmacological treatment of depression consists of stages of trial and error, with less than 40% of patients achieving remission during first medication trial. However, in a large, randomized-controlled trial (RCT) in the U.S. ("GUIDED"), significant improvements in response and remission rates were observed in patients who received treatment guided by combinatorial pharmacogenomic testing, compared to treatment-as-usual (TAU). Here we present results from the Canadian "GAPP-MDD" RCT. This 52-week, 3-arm, multi-center, participant- and rater-blinded RCT evaluated clinical outcomes among patients with depression whose treatment was guided by combinatorial pharmacogenomic testing compared to TAU. The primary outcome was symptom improvement (change in 17-item Hamilton Depression Rating Scale, HAM-D17) at week 8. Secondary outcomes included response (≥50% decrease in HAM-D17) and remission (HAM-D17 ≤ 7) at week 8. Numerically, patients in the guided-care arm had greater symptom improvement (27.6% versus 22.7%), response (30.3% versus 22.7%), and remission rates (15.7% versus 8.3%) compared to TAU, although these differences were not statistically significant. Given that the GAPP-MDD trial was ultimately underpowered to detect statistically significant differences in patient outcomes, it was assessed in parallel with the larger GUIDED RCT. We observed that relative improvements in response and remission rates were consistent between the GAPP-MDD (33.0% response, 89.0% remission) and GUIDED (31.0% response, 51.0% remission) trials. Together with GUIDED, the results from the GAPP-MDD trial indicate that combinatorial pharmacogenomic testing can be an effective tool to help guide depression treatment in the context of the Canadian healthcare setting (ClinicalTrials.gov NCT02466477).

Subanesthetic ketamine infusions for suicide ideation in patients with bipolar and unipolar treatment refractory depression.

We evaluated the effects of repeated subanesthetic ketamine infusions on suicidal ideation (SI) in patients with major depression. 82 subjects with treatment-resistant unipolar and bipolar depression completed a two-site open-label case-series of repeated (up to four weeks) infusions of ketamine (0.5 mg/kg). Ketamine produced a significant reduction in SI as early as one hour (71.1%) and up to 1-week post-infusion (60.4%), accompanied by a reduction in overall depressive symptoms which were maintained until the 4th week. The observed anti-suicidal effect was independent of mood changes, as patients whose mood did not respond still exhibited significantly less SI than baseline.

A minimum evaluation protocol and stepped-wedge cluster randomized trial of ACCESS Open Minds, a large Canadian youth mental health services transformation project.

BACKGROUND: Many Canadian adolescents and young adults with mental health problems face delayed detection, long waiting lists, poorly accessible services, care of inconsistent quality and abrupt or absent inter-service transitions. To address these issues, ACCESS Open Minds, a multi-stakeholder network, is implementing and systematically evaluating a transformation of mental health services for youth aged 11 to 25 at 14 sites across Canada. The transformation plan has five key foci: early identification, rapid access, appropriate care, the elimination of age-based transitions between services, and the engagement of youth and families. METHODS: The ACCESS Open Minds Research Protocol has multiple components including a minimum evaluation protocol and a stepped-wedge cluster randomized trial, that are detailed in this paper. Additional components include qualitative methods and cost-effectiveness analyses. The services transformation is being evaluated at all sites via a minimum evaluation protocol. Six sites are participating in the stepped-wedge trial whereby the intervention (a service transformation along the key foci) was rolled out in three waves, each commencing six months apart. Two sites, one high-population and one low-population, were randomly assigned to each of the three waves, i.e., randomization was stratified by population size. Our primary hypotheses pertain to increased referral numbers, and reduced wait times to initial assessment and to the commencement of appropriate care. Secondary hypotheses pertain to simplified pathways to care; improved clinical, functional and subjective outcomes; and increased satisfaction among youth and families. Quantitative measures addressing these hypotheses are being used to determine the effectiveness of the intervention. DISCUSSION: Data from our overall research strategy will help test the effectiveness of the ACCESS Open Minds transformation, refine it further, and inform its scale-up. The process by which our research strategy was developed has implications for the practice of research itself in that it highlights the need to actively engage all stakeholder groups and address unique considerations in designing evaluations of complex healthcare interventions in multiple, diverse contexts. Our approach will generate both concrete evidence and nuanced insights, including about the challenges of conducting research in real-world settings. More such innovative approaches are needed to advance youth mental health services research. TRIAL REGISTRATION NUMBER: Clinicaltrials.gov, ISRCTN23349893 (Retrospectively registered: 16/02/2017).

Transforming youth mental health care in a semi-urban and rural region of Canada: A service description of ACCESS Open Minds Chatham-Kent.

AIM: This study describes how mental health services for youth are being transformed within the context of a semi-urban and rural region of Canada (Chatham-Kent, Ontario), based on the framework of ACCESS Open Minds (ACCESS OM), a pan-Canadian youth mental health research and evaluation network. METHODS: Transformation has focused on the five key objectives of ACCESS OM, namely early identification, rapid access, appropriate care, continuity of care, and youth and family engagement. A community mapping process was conducted at the beginning of the transformation to help develop a comprehensive inventory of services, identify challenges and optimize partnerships to address the five key objectives. RESULTS: The following strategies represent key elements in the transformation: coordination and partnerships between hospital, community and voluntary organizations, as well as different sectors of the community (e.g., Child and Youth Services, Education, Community Safety and Correctional Services, CSCS); working with local champions (e.g., Youth Diversion Officer and the Mental Health and Addictions Nurse in the school sectors); establishing a youth-friendly space in a central part of the community, where services are co-located and operate within an open-concept design; training of ACCESS Clinicians to conduct an initial assessment; engaging youth and family in service-level recruitment, planning, daily operations, and evaluation, including hiring of youth and family peer navigators; and, engaging the community through awareness and educational events. CONCLUSIONS: The success of this transformation needs to be measured on various outcome parameters, but it is notable that neighbouring communities are already beginning to implement a similar model.

Canadian response to need for transformation of youth mental health services: ACCESS Open Minds (Esprits ouverts).

AIM: Youth mental health is of paramount significance to society globally. Given early onset of mental disorders and the inadequate access to appropriate services, a meaningful service transformation, based on globally recognized principles, is necessary. The aim of this paper is to describe a national Canadian project designed to achieve transformation of mental health services and to evaluate the impact of such transformation on individual and system related outcomes. METHOD: We describe a model for transformation of services for youth with mental health and substance abuse problems across 14 geographically, linguistically and culturally diverse sites, including large and small urban, rural, First Nations and Inuit communities as well as homeless youth and a post-secondary educational setting. The principles guiding service transformation and objectives are identical across all sites but the method to achieve them varies depending on prevailing resources, culture, geography and the population to be served and how each community can best utilize the extra resources for transformation. RESULTS: Each site is engaged in community mapping of services followed by training, active stakeholder engagement with youth and families, early case identification initiatives, providing rapid access (within 72 hours) to an assessment of the presenting problems, facilitating connection to an appropriate service within 30 days (if required) with no transition based on age within the 11 to 25 age group and a structured evaluation to track outcomes over the period of the study. CONCLUSIONS: Service transformation that is likely to achieve substantial change involves very detailed and carefully orchestrated processes guided by a set of values, principles, clear objectives, training and evaluation. The evidence gathered from this project can form the basis for scaling up youth mental health services in Canada across a variety of environments.

Cultural and Contextual Adaptation of an eHealth Intervention for Youth Receiving Services for First-Episode Psychosis: Adaptation Framework and Protocol for Horyzons-Canada Phase 1.

BACKGROUND: eHealth interventions have the potential to address challenges related to access, service engagement, and continuity of care in the delivery of mental health services. However, the initial development and evaluation of such interventions can require substantive amounts of financial and human resource investments to bring them to scale. Therefore, it may be warranted to pay greater attention to policy, services, and research with respect to eHealth platforms that have the potential to be adapted for use across settings. Yet, limited attention has been placed on the methods and processes for adapting eHealth interventions to improve their applicability across cultural, geographical, and contextual boundaries. OBJECTIVE: In this paper, we describe an adaptation framework and protocol to adapt an eHealth intervention designed to promote recovery and prevent relapses in youth receiving specialized services for first-episode psychosis. The Web-based platform, called Horyzons, was initially developed and tested in Australia and is now being prepared for evaluation in Canada. METHODS: Service users and service providers from 2 specialized early intervention programs for first-episode psychosis located in different provinces will explore a beta-version of the eHealth intervention through focus group discussions and extended personal explorations to identify the need for, and content of contextual and cultural adaptations. An iterative consultation process will then take place with service providers and users to develop and assess platform adaptations in preparation for a pilot study with a live version of the platform. RESULTS: Data collection was completed in August 2017, and analysis and adaptation are in process. The first results of the study will be submitted for publication in 2018 and will provide preliminary insights into the acceptability of the Web-based platform (eg, perceived use and perceived usefulness) from service provider and service user perspectives. The project will also provide knowledge about the adaptations and process needed to prepare the platform for evaluation in Canada. CONCLUSIONS: This study contributes to an important gap in the literature pertaining to the specific principles, methods, and steps involved in adapting eHealth interventions for implementation and evaluation across a diverse range of cultural, geographical, and health care settings.

Adjunctive Vitamin D in the treatment of non-remitted depression: Lessons from a failed clinical trial.

BACKGROUND: Many patients with depression fail to achieve remission after several consecutive treatments. Vitamin D deficiency is prevalent and new research suggests that it may have an impact on mood, primarily through an effect on neurotransmitters. Numerous observational studies suggest a relationship between low levels of vitamin D and increased incidence and severity of mood disorders. A small number of pilot studies have been undertaken but lack rigorous methodology required to draw conclusions about a clinical role for this nutrient in treatment resistant depression. METHODS: This study was designed as a randomized, double-blind, placebo controlled intervention study administering a weekly (bolus) dose of 28 000IU of Vitamin D3 or placebo to 125 patients with non-remitted depression adjunct to current antidepressant medication. Patients were followed weekly for eight weeks plus a one month follow up. Outcomes measured included depression severity, serum vitamin D levels and safety. Due to slow recruitment during the first season, amendments were made. These included extending the age range to 18-75 and removing the requirement for failing to respond to one pharmacologic antidepressant agent. The protocol was amended to reduce the burden on participants by changing the in-office visits to bi-weekly. Three additional tertiary psychiatric clinics were also added as trial sites. RESULTS: Over three recruitment period years (fall/winter), a total of 148 participants completed screening, 24 (16.2%) of whom qualified to participate in the study. Use of too many or no psychiatric medications, comorbid exclusionary psychiatric conditions, current use of a vitamin D supplement, and lack of participant compensation were the predominant reasons for ineligibility or unwillingness to participate. 9 participants were successfully enrolled in the study, 7 (77.8%) of whom completed the trial as per the protocol. After the third season, futility was declared based on inability to enroll participants. The sample size of enrolled participants (7/125, 5.6%) lacks power to conduct a full assessment of findings. DISCUSSION: High accessibility of vitamin D, as well as a growing lack of equipoise in patients and clinicians about the potential ubiquitous benefits of vitamin D for Canadians, not just for mood disorders, resulted in a large proportion of ineligible potential participants. Limited funding provided to studies on natural health products hampered recruitment. The labile and fluctuating nature of non-remitted depression as well as frequent co-morbid conditions creates additional challenges for conducting trials in this population. Future studies assessing vitamin D in depression should consider our experiences in design and conduct of research. Innovations in clinical trial design such as preference trials or accepting patients already using vitamin D but not achieving an optimal target value are potential solutions to some of these challenges.

Exploring the views of emergency department staff on the use of videoconferencing for mental health emergencies in southwestern Ontario.

Patients presenting to a rural emergency department (ED) with mental health symptoms have difficulty accessing services of mental health professionals [1,2]. Videoconferencing (VC) has been found to improve patient access to health services that require specialist care in rural EDs [3,4,5]. Although previous studies highlight the benefit of using VC for patients presenting with mental health emergencies, no study has investigated the current views and use of VC for mental health emergencies in EDs in Southwestern Ontario [3,5,6]. To explore the views of ED staff regarding the use of VC in mental health emergencies, structured telephone interviews were conducted with representatives from EDs in the Erie St. Clair and Southwest Local Health Integration Networks (LHIN). Participants noted that using VC for mental health emergencies may improve patient experience and benefit crisis response teams. VC was perceived by some participants as a means to expedite the direct assessment of a patient presenting with a mental health emergency by a mental health specialist. However several participants stated that using VC for mental health emergencies strains ED resources. Lack of use and difficulty accessing a psychiatrist were identified as potential barriers to implementing the use of VC for mental health emergencies.

Risperidone long-acting injection in the treatment of schizophrenia: 24-month results from the electronic Schizophrenia Treatment Adherence Registry in Canada.

OBJECTIVE: To assess outcomes over 24 months in Canadian patients with schizophrenia initiated on risperidone long-acting injection (RLAI) and participating in the electronic Schizophrenia Treatment Adherence Registry (e-STAR). MATERIALS AND METHODS: Patients with schizophrenia or schizoaffective disorder were enrolled from 24 sites after an independent decision to initiate RLAI. Subsequent patient management was based on usual clinical practice at each site and was not protocol-driven. Relevant data were collected retrospectively by chart review for 12 months prior to RLAI and prospectively for 24 months following RLAI initiation. RESULTS: Patients (n=188) had a mean age of 39.2 years, were 66.3% male, and 27.7% were inpatients at baseline. Twenty-four months after initiating therapy (initial dose =28.7 mg), 34.1% (95% confidence interval 27.2%-42.2%) of patients had discontinued RLAI with a mean time to discontinuation of 273.4±196 days. Over the treatment period, there were significant (P<0.001) changes from baseline in Clinical Global Impression-Severity (CGI-S; 3.48 versus [vs] 4.31 at baseline), Global Assessment of Functioning (GAF; 56.1 vs 48.1), and Personal and Social Performance (PSP; 59.1 vs 46.9) scale scores. In addition, after 12 months, there were significant (P<0.001) decreases in the percentage of patients hospitalized (23.9% vs 58.5% pre-RLAI), mean length of stay (11.4 vs 30.4 days), and number of hospitalizations (0.32 vs 0.87) compared to the 12-month pre-RLAI period. Reductions in hospitalization continued into the second 12 months of therapy, when only 9% of patients were hospitalized and mean length of stay was 2.0 days. CONCLUSION: In a routine clinical practice setting, patients switched to RLAI showed significant improvements in clinical outcomes and in global and social functioning, and hospitalization was significantly reduced. The data confirm that RLAI provides effective long-term management of schizophrenia in Canada.

Antipsychotic switching: results from a one-year prospective, observational study of patients with schizophrenia.

OBJECTIVE: The Health Outcomes of a Canadian Community Cohort (HOCCC) study is a 1-year prospective observational study of outpatients with schizophrenia or related psychotic disorders. The purpose of the study was to compare effectiveness of antipsychotic treatment as measured by 1-year treatment completion rates. DESIGN AND METHODS: Patients (N = 929) were enrolled if in the course of usual clinical practice they switched to a second-generation antipsychotic (SGA). Observational data were collected for up to 1 year. The primary analysis compared 1-year treatment-completion rates for the olanzapine cohort with the other SGA cohort (quetiapine, risperidone, clozapine), using a chi-squared test. RESULTS: Of 929 patients enrolled, 64.8% (516/796) of evaluable patients completed 1 year of treatment. There was no statistically significant difference in the proportion of treatment completers between the olanzapine cohort (67.4%, 256/380) and the other SGA cohort (62.5%, 260/416). Treatment-completion rates were risperidone 62.0% (127/205), quetiapine 63.7% (123/193) and clozapine 55.6% (10/18). Antipsychotic polypharmacy was common. Patients treated with olanzapine or risperidone had significantly higher increases in BMI than quetiapine-treated patients. There were no major differences between olanzapine monotherapy and pooled other SGA monotherapy groups in status of extrapyramidal symptoms from baseline to endpoint. CONCLUSIONS: Olanzapine and other SGAs exhibited similar rates of 1-year treatment completion. Further study of medication combinations is needed, given their perceived clinical value, and the high frequency of antipsychotic polypharmacy in clinical practice. LIMITATIONS: As most patients received several psychotropics and power was reduced in monotherapy analyses, comparisons between cohorts must be interpreted cautiously. Comparisons between individual antipsychotics were post hoc and not powered a priori. Accuracy and completeness of adverse event information for drugs other than olanzapine is limited.