Correction: Effects of a WHO-guided digital health intervention for depression in Syrian refugees in Lebanon: A randomized controlled trial.

[This corrects the article DOI: 10.1371/journal.pmed.1004025.].

Exploring the meaning of unresolved loss and trauma in more than 1,000 Adult Attachment Interviews.

Unresolved states of mind regarding experiences of loss/abuse (U/d) are identified through lapses in the monitoring of reasoning, discourse, and behavior surrounding loss/abuse in response to the Adult Attachment Interview. Although the coding system for U/d has been widely used for decades, the individual indicators of unresolved loss/abuse have not been validated independently of the development sample. This study examined the psychometric validity of U/d, using individual participant data from 1,009 parent-child dyads across 13 studies. A latent class analysis showed that subsets of commonly occurring U/d indicators could differentiate interviewees with or without unresolved loss/abuse. Predictive models suggested a psychometric model of U/d consisting of a combination of these common indicators, with disbelief and psychologically confused statements regarding loss being especially important indicators of U/d. This model weakly predicted infant disorganized attachment. Multilevel regression analysis showed no significant association between ratings of unresolved other trauma and infant disorganized attachment, over and above ratings of unresolved loss/abuse. Altogether, these findings suggest that the coding system of U/d may have been overfitted to the initial development sample. Directions for further articulation and optimization of U/d are provided.

Effects of a WHO-guided digital health intervention for depression in Syrian refugees in Lebanon: A randomized controlled trial.

BACKGROUND: Most displaced people with mental disorders in low- and middle-income countries do not receive effective care, and their access to care has deteriorated during the Coronavirus Disease 2019 (COVID-19) pandemic. Digital mental health interventions are scalable when digital access is adequate, and they can be safely delivered during the COVID-19 pandemic. We examined whether a new WHO-guided digital mental health intervention, Step-by-Step, in which participants were supported by a nonspecialist helper, was effective in reducing depression among displaced people in Lebanon. METHODS AND FINDINGS: We conducted a single-blind, 2-arm pragmatic randomized clinical trial, comparing guided Step-by-Step with enhanced care as usual (ECAU) among displaced Syrians suffering from depression and impaired functioning in Lebanon. Primary outcomes were depression (Patient Health Questionnaire, PHQ-9) and impaired functioning (WHO Disability Assessment Schedule-12, WHODAS) at posttreatment. Secondary outcomes included subjective well-being, anxiety, post-traumatic stress, and self-described problems. A total of 569 displaced people from Syria with depression (PHQ-9 ≥ 10) and impaired functioning (WHODAS > 16) were randomized to Step-by-Step (N = 283; lost to follow-up: N = 167) or ECAU (N = 286; lost to follow-up: 133). Participants were considered to be lost to follow-up when they did not fill in the outcome measures at posttest or follow-up. Recruitment started on December 9, 2019 and was completed on July 9, 2020. The last follow-up assessments were collected in December 2020. The study team had access to the online platform, where they could see treatment arm assignment for each participant. All questionnaires were completed by participants online. Intention-to-treat (ITT) analyses showed intervention effects on depression (standardized mean differences [SMDs]: 0.48; 95% CI: 0.26; 0.70; p < 0.001), impaired functioning (SMD: 0.35; 95% CI: 0.14; 0.56; p < 0.001), post-traumatic stress (SMD: 0.36; 95% CI: 0.16; 0.56; p < 0.001), anxiety (SMD: 0.46; 95% CI: 0.24; 0.68; p < 0.001), subjective well-being (SMD: 0.47; 95% CI: 0.26; 0.68; p < 0.001), and self-identified personal problems (SMD: 0.49; 95% CI 0.28; 0.70; p < 0.001). Significant effects on all outcomes were maintained at 3 months follow-up. During the trial, one serious adverse event occurred, unrelated to the intervention. The main limitation of the current trial is the high dropout rate. CONCLUSIONS: In this study, we found that a guided, digital intervention was effective in reducing depression in displaced people in Lebanon. The guided WHO Step-by-Step intervention we examined should be made available to communities of displaced people that have digital access. TRIAL REGISTRATION: ClinicalTrials.gov NCT03720769.

Recurrent individual treatment assignment: a treatment policy approach to account for heterogeneous treatment effects.

Longitudinal randomized controlled trials generally assign individuals randomly to interventions at baseline and then evaluate how differential average treatment effects evolve over time. This study shows that longitudinal settings could benefit from Recurrent Individual Treatment Assignment (RITA) instead, particularly in the face of (dynamic) heterogeneous treatment effects. Focusing on the optimization of treatment assignment, rather than on estimating treatment effects, acknowledges the presence of unobserved heterogeneous treatment effects and improves overall intervention response when compared to intervention policies in longitudinal settings based on Randomized Controlled Trials (RCTs)-derived average treatment effects. This study develops a RITA-algorithm and evaluates its performance in a multi-period simulation setting, considering two alternative interventions and varying the extent of unobserved heterogeneity in individual treatment response. The results show that RITA learns quickly, and adapts individual assignments effectively. If treatment heterogeneity exists, the inherent focus on both exploit and explore enables RITA to outperform a conventional assignment strategy that relies on RCT-derived average treatment effects.

Automated app-based augmented reality cognitive behavioral therapy for spider phobia: Study protocol for a randomized controlled trial.

BACKGROUND: Fear of spiders, or Arachnophobia, is one of the most common specific phobias. The gold standard treatment, in vivo exposure therapy, is effective, but comes with significant limitations, including restricted availability, high costs, and high refusal rates. Novel technologies, such as augmented reality, may help to overcome these limitations and make Exposure Therapy more accessible by using mobile devices. OBJECTIVE: This study will use a Randomized Controlled Trial design to investigate whether ZeroPhobia: Arachnophobia, a 6-week Augmented Reality Exposure Therapy smartphone self-help application, can effectively reduce spider phobia symptoms. Additionally, we will examine user-friendliness of the application and the effect of usage intensity and presence on treatment outcome. METHODS: This study is registered in the Netherlands Trial Registry under NL70238.029.19 (Trial NL9221). Ethical approval was received on October 11, 2019. One-hundred-twelve participants (age 18-64, score ≥ 59) on the Fear of Spiders Questionnaire [FSQ] will be recruited from the general Dutch population and randomly assigned to a treatment or waitlist control group. The ZeroPhobia application can be accessed on users' smartphone. Baseline, post-test (i.e., at six weeks), 3- and 12-month follow-up assessments will be done, each including the Fear of Spiders Questionnaire as the main outcome measure as well as additional measures of anxiety, depression, user-friendliness, and presence as secondary measures and covariates. RESULTS: The study was funded on September 25, 2018. Data collection started in September 2021 and the study is expected to run until September 2022. CONCLUSIONS: Our study will improve our understanding of the efficacy and feasibility of providing Exposure Therapy for spider phobia using an Augmented Reality self-help application, with the intention of making mental health care more accessible.

Guided digital health intervention for depression in Lebanon: randomised trial.

BACKGROUND: Most people with mental disorders in communities exposed to adversity in low-income and middle-income countries (LMICs) do not receive effective care. Digital mental health interventions are scalable when digital access is adequate, and can be safely delivered during the COVID-19 pandemic. OBJECTIVE: To examine the effects of a new WHO-guided digital mental health intervention, Step-by-Step, supported by a non-specialist helper in Lebanon, in the context of concurring economic, humanitarian and political crises, a large industrial disaster and the COVID-19 pandemic. METHODS: We conducted a single-blind, two-arm pragmatic randomised trial, comparing guided Step-by-Step with enhanced care as usual (ECAU) among people suffering from depression and impaired functioning. Primary outcomes were depression (Patient Health Questionnaire 9 (PHQ-9)) and impaired functioning (WHO Disability Assessment Schedule-12 (WHODAS)) at post-treatment. FINDINGS: 680 people with depression (PHQ-9>10) and impaired functioning (WHODAS>16) were randomised to Step-by-Step or ECAU. Intention-to-treat analyses showed effects on depression (standardised mean differences, SMD: 0.71; 95% CI: 0.45 to 0.97), impaired functioning (SMD: 0.43; 95% CI: 0.21 to 0.65), post-traumatic stress (SMD: 0.53; 95% CI: 0.27 to 0.79), anxiety (SMD: 0.74; 95% CI: 0.49 to 0.99), subjective well-being (SMD: 0.37; 95% CI: 0.12 to 0.62) and self-identified personal problems (SMD: 0.56; 95% CI 0.29 to 0.83). Significant effects on all outcomes were retained at 3-month follow-up. CONCLUSIONS: Guided digital mental health interventions can be effective in the treatment of depression in communities exposed to adversities in LMICs, although some uncertainty remains because of high attrition. CLINICAL IMPLICATIONS: Guided digital mental health interventions should be considered for implementation in LMICs. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT03720769.

Virtual Reality Self-help Treatment for Aviophobia: Protocol for a Randomized Controlled Trial.

BACKGROUND: Aviophobia (the fear of flying) can greatly impact the daily life functioning of people with the condition. Traditional exposure-based treatment is hampered by the limited availability of airplane practice situations, which is a result of economical and practical concerns. Easily accessible and low-cost virtual reality exposure therapy may address these challenges. OBJECTIVE: The purpose of our study is to investigate the effectiveness of ZeroPhobia: Aviophobia (a self-help mobile app-based treatment) in reducing flight anxiety symptoms and depressive and anxiety symptoms. We will also investigate the effects of usage intensity, the sense of immersion, inherent absorption ability, and perceived user-friendliness on the treatment effect. METHODS: Participants (N=114) who are aged 18-64 years and experience at least mild symptoms of aviophobia will be recruited from the general Dutch population and randomized into a treatment group or waitlist control group. By using their own phones and rudimentary mobile virtual reality headsets, participants will receive six modules of psychoeducation and cognitive behavioral therapy, which will include six levels of virtual reality exposure therapy over a period of 6 weeks. Assessments will be conducted at baseline, posttest (ie, after 6 weeks), and 3- and 12-month follow-ups. The primary outcome measure of our study is the Flight Anxiety Situations Questionnaire. The secondary outcome measures include anxiety and depression measures and additional covariates (including usage intensity, the degree of immersion, etc). We will test treatment effectiveness by conducting an intention-to-treat analysis and estimating average treatment effects on the treated. The mechanisms of treatment effect will also be explored. RESULTS: The study was funded on September 25, 2018. Ethical approval was received on October 11, 2019. Recruitment closed on May 7, 2020. CONCLUSIONS: Our study will further the scientific understanding and clinical implications of technology's current ability to aid in providing effective, accessible treatment for the fear of flying. TRIAL REGISTRATION: Netherlands Trial Registry NL70238.029.19; https://www.trialregister.nl/trial/8257. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/22008.

Pain, cognition and disability in advanced multiple sclerosis.

OBJECTIVES: In patients with multiple sclerosis (MS), a relationship between physical disability and pain has been observed. In addition a relationship between physical disability and cognition in MS has been suggested. However, cognitive functions and pain appear not to be correlated in MS patients. Therefore, we examined whether a possible relationship between pain and cognitive functioning may exist, and if so, if such a relationship is mediated by physical disability. METHODS: Forty-five MS patients with chronic pain, and in an advanced stage of the disease were included. Physical disabilities were assessed by the Expanded Disability Status Scale (EDSS). Episodic memory was assessed by means of the Eight Words test, and Face and Picture Recognition. Executive functions (EF) were examined by Digit Span Backward for working memory, and the Rule Shift Cards and Category Fluency test for cognitive flexibility. Pain Intensity and Pain Affect were assessed by means of visual analogue scales and one verbal pain scale and mood (depression, anxiety) by the Beck Depression Inventory and the Symptom Check List (SCL-90). The research questions were analyzed by means of regression analyses and the Sobel test for mediation. RESULTS: A significant relationship was found between Pain Affect and EF, but that relationship was not mediated by physical disabilities (EDSS). In addition, Pain Intensity and EF showed a significant relationship but only in combination with physical disabilities (EDSS). Finally, mood was related to pain affect. DISCUSSION: The findings suggest that the lower the EF, exclusively or in combination with more physical disabilities, the more the patient may suffer from pain. IMPLICATIONS: The more one is cognitively and physically impaired, the more one might suffer from pain, and, the less one is able to communicate pain. The latter could put MS patients at risk for underdiagnosing and undertreatment of pain.

Step-by-step: Feasibility randomised controlled trial of a mobile-based intervention for depression among populations affected by adversity in Lebanon.

BACKGROUND: E-mental health interventions may help to bridge the mental health treatment gap. Evidence on their effectiveness is compelling in high-income countries. Not enough evidence has been generated on their use with communities affected by adversity in low- and middle-income countries. The World Health Organization (WHO), the National Mental Health Programme (NMMP) at Ministry of Public Health (MoPH) in Lebanon and other partners have adapted a WHO intervention called Step-by-Step for use with Lebanese and displaced people living in Lebanon. Step-by-Step is a minimally guided, internet-based intervention for adults with depression. In this study, a feasibility randomised controlled trial (RCT) and a qualitative process evaluation were conducted to explore the feasibility and the acceptability of the research methods, and the intervention, in preparation for two fully powered trials to assess the effectiveness and cost-effectiveness of Step-by-Step in Lebanon. METHOD: Participants were recruited through social media. Inclusion criteria were: being able to understand and speak Arabic or English; access to an internet connected device; aged over 18; living in Lebanon; scores above cut-off on the Patient Health Questionnaire and the WHO Disability Assessment Schedule 2.0. Participants were randomly assigned to the intervention or enhanced care as usual. They completed post-assessments eight weeks after baseline, and follow-up assessments another three months later. Primary outcomes were depression and level of functioning, secondary outcomes were anxiety, post-traumatic stress, and well-being. Qualitative interviews were conducted to evaluate the feasibility and acceptability of the research procedures and the intervention. RESULTS: A total of N = 138 participants, including 33 Syrians, were recruited and randomised into two equal groups. The dropout rate was higher in the control group (73% post- and 82% follow-up assessment) than in the intervention group (63% post- and 72% follow-up assessment). The intervention was perceived as relevant, acceptable and beneficial to those who completed it. Suggestions were made to further adapt the content and to make the intervention more engaging. Statistical analyses were conducted despite the small sample size. Complete cases analysis showed a statistically significant symptom reduction in depression, anxiety, disability, and post-traumatic stress, and statistically significant improvement in well-being and functioning. Intention-to-treat analysis revealed non-significant effects. CONCLUSION: The research design, methods and procedures are feasible and acceptable in the context of Lebanon and can be applied in the RCTs. Preliminary findings suggest that Step-by-Step may be effective in reducing symptoms of depression and anxiety and improving functioning and well-being.

Evaluating the Effectiveness of an E-Mental Health Intervention for People Living in Lebanon: Protocol for Two Randomized Controlled Trials.

BACKGROUND: The lack of availability of evidence-based services for people exposed to adversity globally has led to the development of psychological interventions with features that will likely make them more scalable. The evidence for the efficacy of e-mental health from high-income countries is compelling, and the use of these interventions could be a way to increase the coverage of evidence-based psychological interventions in low- and middle-income countries. Step-by-Step is a brief (5-session) intervention proposed by the World Health Organization as an innovative approach to reducing the suffering and disability associated with depression. OBJECTIVE: This study aims to evaluate the effectiveness and cost-effectiveness of a locally adapted version of Step-by-Step with Syrian nationals (trial 1) and Lebanese nationals and other populations residing in Lebanon (trial 2). METHODS: This Step-by-Step trial involves 2 parallel, two-armed, randomized controlled trials comparing the e-intervention Step-by-Step to enhanced care as usual in participants with depressive symptoms and impaired functioning. The randomized controlled trials are designed and powered to detect effectiveness in 2 populations: Syrians in Lebanon (n=568) and other people residing in Lebanon (n=568; Lebanese nationals and other populations resident in Lebanon). The primary outcomes are depressive symptomatology (measured with the Patient Health Questionnaire-9) and functioning (measured with the World Health Organization Disability Assessment Scale 2.0). Secondary outcomes include anxiety symptoms, posttraumatic stress disorder symptoms, personalized measures of psychosocial problems, subjective well-being, and economic effectiveness. Participants are mainly recruited through online advertising. Additional outreach methods will be used if required, for example through dissemination of information through partner agencies and organizations. They can access the intervention on a computer, tablet, and mobile phone through a hybrid app. Step-by-Step has 5 sessions, and users are guided by trained nonspecialist "e-helpers" providing phone-based or message-based support for around 15 minutes a week. RESULTS: The trials were funded in 2018. The study protocol was last verified June 20, 2019 (WHO ERC.0002797) and registered with ClinicalTrials.gov (NCT03720769). The trials started recruitment as of December 9, 2019, and all data collection was completed in December 2020. CONCLUSIONS: The Step-by-Step trials will provide evidence about the effectiveness of an e-mental health intervention in Lebanon. If the intervention proves to be effective, this will inform future scale-up of this and similar interventions in Lebanon and in other settings across the world. TRIAL REGISTRATION: ClinicalTrials.gov NCT03720769; https://clinicaltrials.gov/ct2/show/NCT03720769. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/21585.

Addressing missing data in randomized clinical trials: A causal inference perspective.

BACKGROUND: The importance of randomization in clinical trials has long been acknowledged for avoiding selection bias. Yet, bias concerns re-emerge with selective attrition. This study takes a causal inference perspective in addressing distinct scenarios of missing outcome data (MCAR, MAR and MNAR). METHODS: This study adopts a causal inference perspective in providing an overview of empirical strategies to estimate the average treatment effect, improve precision of the estimator, and to test whether the underlying identifying assumptions hold. We propose to use Random Forest Lee Bounds (RFLB) to address selective attrition and to obtain more precise average treatment effect intervals. RESULTS: When assuming MCAR or MAR, the often untenable identifying assumptions with respect to causal inference can hardly be verified empirically. Instead, missing outcome data in clinical trials should be considered as potentially non-random unobserved events (i.e. MNAR). Using simulated attrition data, we show how average treatment effect intervals can be tightened considerably using RFLB, by exploiting both continuous and discrete attrition predictor variables. CONCLUSIONS: Bounding approaches should be used to acknowledge selective attrition in randomized clinical trials in acknowledging the resulting uncertainty with respect to causal inference. As such, Random Forest Lee Bounds estimates are more informative than point estimates obtained assuming MCAR or MAR.

Analysis of Usage Data from a Self-Guided App-Based Virtual Reality Cognitive Behavior Therapy for Acrophobia: A Randomized Controlled Trial.

This study examined user engagement with ZeroPhobia, a self-guided app-based virtual reality (VR) Cognitive Behavior Therapy for acrophobia symptoms using cardboard VR viewers. Dutch acrophobic adults (n = 96) completed assessments at baseline and immediately following treatment. Primary outcome measures were the Acrophobia Questionnaire (AQ) and the Igroup Presence Questionnaire (IPQ). Usage data consisted of number of VR sessions practiced, practice time, and fear ratings directly after practicing. Results show that of the 66 participants who played at least one level, the majority continued to finish all levels, spending on average 24.4 min in VR. Self-reported fear consistently decreased between the start and finish of levels. Post-test AQ scores depended quadratically on time spent in VR. Higher pre-test AQ scores were significantly associated with subjective anxiety after the first level and a reduction of post-test AQ scores, but not with number of sessions, suggesting it might be more beneficial to play one level for a longer time period instead of practicing many VR levels. Results also show an optimum exposure level at which increasing practice time does not result in increased benefit. Self-guided VR acrophobia treatment is effective and leads to consistent reductions in self-reported anxiety both between levels and after treatment. Most participants progressed effectively to the highest self-exposure level, despite the absence of a therapist.

Effectiveness of Self-guided App-Based Virtual Reality Cognitive Behavior Therapy for Acrophobia: A Randomized Clinical Trial.

Importance: Globally, access to evidence-based psychological treatment is limited. Innovative self-help methods using smartphone applications and low-cost virtual reality have the potential to significantly improve the accessibility and scalability of psychological treatments. Objective: To examine the effectiveness of ZeroPhobia, a fully self-guided app-based virtual reality cognitive behavior therapy (VR CBT) using low-cost (cardboard) virtual reality goggles compared with a wait-list control group and to determine its user friendliness. Design, Setting, and Participants: In a single-blind randomized clinical trial, participants were enrolled between March 24 and September 28, 2017, and randomly assigned (1:1) by an independent researcher to either VR CBT app or a wait-list control group. A total of 193 individuals aged 18 to 65 years from the Dutch general population with acrophobia symptoms and access to an Android smartphone participated. The 6 animated modules of the VR-CBT app and gamified virtual reality environments were delivered over a 3-week period in participants' natural environment. Assessments were completed at baseline, immediately after treatment, and at 3-month follow-up. Analysis began April 6, 2018, and was intention to treat. Intervention: Self-guided app-based VR CBT. Main Outcomes and Measures: The primary outcome measure was the Acrophobia Questionnaire. The hypothesis was formulated prior to data collection. Results: In total, 193 participants (129 women [66.84%]; mean [SD] age, 41.33 [13.64] years) were randomly assigned to intervention (n = 96) or a wait-list control group (n = 97). An intent-to-treat analysis showed a significant reduction of acrophobia symptoms at posttest at 3 months for the VR-CBT app compared with the controls (b = -26.73 [95% CI, -32.12 to -21.34]; P < .001; d = 1.14 [95% CI, 0.84 to 1.44]). The number needed to treat was 1.7. Sensitivity and robustness analysis confirmed these findings. Pretreatment attrition was 22 of 96 (23%) because of smartphone incompatibility. Of the 74 participants who started using the VR-CBT app, 57 (77%) completed the intervention fully. Conclusions and Relevance: A low-cost fully self-guided app-based virtual reality cognitive behavioral therapy with rudimentary virtual reality goggles can produce large acrophobia symptom reductions. To our knowledge, this study is the first to show that virtual reality acrophobia treatment can be done at home without the intervention of a therapist. Trial Registration: Trialregister.nl identifier: NTR6442.