Current and Emerging Technologies to Address the Placebo Response Challenge in CNS Clinical Trials: Promise, Pitfalls, and Pathways Forward.

Excessive placebo response rates have long been a major challenge for central nervous system (CNS) drug discovery. As CNS trials progressively shift toward digitalization, decentralization, and novel remote assessment approaches, questions are emerging about whether innovative technologies can help mitigate the placebo response. This article begins with a conceptual framework for understanding placebo response. We then critically evaluate the potential of a range of innovative technologies and associated research designs that might help mitigate the placebo response and enhance detection of treatment signals. These include technologies developed to directly address placebo response; technology-based approaches focused on recruitment, retention, and data collection with potential relevance to placebo response; and novel remote digital phenotyping technologies. Finally, we describe key scientific and regulatory considerations when evaluating and selecting innovative strategies to mitigate placebo response. While a range of technological innovations shows potential for helping to address the placebo response in CNS trials, much work remains to carefully evaluate their risks and benefits.

Impact and efficiency of treatment across two PTSD clinical trials comparing in-person and telehealth service delivery formats.

The intent of this study is to examine treatment impact and efficiency observed when cognitive behavioral treatments for posttraumatic stress disorder (PTSD) are delivered in-person or using telehealth. This study pooled data from 268 veterans enrolled in two PTSD clinical trials. In both trials, treatment was delivered using in-home telehealth (telehealth arm), in-home in-person (in-home arm), and in-office care, where patients traveled to the Department of Veterans Affairs for either office-based telehealth or office-based in-person care (office arm). Average age was 44 (SD = 12.57); 80.9% were males. The PTSD Checklist for DSM-5 (PCL-5) was used to assess symptom severity. Treatment impact was measured by (a) the proportion of participants who completed at least eight treatment sessions and (b) the proportion with a reliable change of ≥ 10 points on the PCL-5. Treatment efficiency was measured by the number of days required to reach the end point. The proportion of participants who attended at least eight sessions and achieved reliable change on the PCL-5 differed across treatment formats (ps < .05). Participants in the in-home (75.4%) format were most likely to attend at least eight treatment sessions, followed by those in the telehealth (58.3%) and office (44.0%) formats, the latter of which required patients to travel. Participants in the in-home (68.3%, p < .001) format were also more likely to achieve reliable change, followed by those in the telehealth (50.9%) and office (44.2%) formats. There were no significant differences in the amount of time to complete at least eight sessions. Delivery of therapy in-home results in a significantly greater likelihood of achieving both an adequate dose of therapy and a reliable decrease in PTSD symptoms compared to telehealth and office formats. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

A Pilot Study Examining Feasibility and Initial Efficacy of Remotely Delivered Cognitive Adaptation Training.

Cognitive Adaptation Training (CAT) is an evidence-based treatment that uses environmental supports including signs, text messages, checklists, smart pill containers, and the organization of belongings to bypass cognitive and motivational impairments and to cue adaptive behavior in the home or work environment. We developed and tested a remote version of CAT to make the treatment available more broadly. Because CAT is focused on working with the individual in their home environment to establish supports, CAT may not be as easy to translate into an effective virtual treatment as talk-therapies. Fifty-six members of managed care were assigned to or given their treatment preference for CAT or Remote CAT (R-CAT) for 6 months. In-person or virtual pill counts were conducted monthly and assessments of habit-formation, symptoms, functioning, and satisfaction were administered every 2 months by independent raters. Analyses using mixed models with repeated measures focused on pre-planned evaluations of within-group change. Adherence improved significantly in R-CAT, functioning improved significantly in CAT and both groups improved significantly on measures of habit-formation and symptoms across 6 months. Higher functioning individuals appeared to choose R-CAT. Satisfaction with treatment was very high in both groups. R-CAT appears to be a potentially effective treatment, particularly for medication follow-though. However, in contrast to decades of previous research, fewer than 20% of eligible Medicaid recipients agreed to participate in the study. This may have been due to recruitment during and immediately post-pandemic.

Unmet needs with antipsychotic treatment in schizophrenia and bipolar I disorder: patient perspectives from qualitative focus groups.

BACKGROUND: Schizophrenia (SZ) and bipolar I disorder (BD-I) are chronic mental health disorders often treated with antipsychotic medications. This qualitative study sought to better understand disease burden and treatment experiences with oral antipsychotic medications in participants living with SZ or BD-I. METHODS: Six 90-min focus groups were conducted with participants diagnosed with SZ or BD-I. Trained moderators facilitated discussions using a semistructured guide. Participants described symptoms, impacts of disease, and experiences with oral antipsychotic medications, whether favourable or unfavourable. RESULTS: Among participants with SZ (n = 15; 3 groups, 5 per group), 53% were male and 33% were white, with a mean of 18.6 years since diagnosis. Of participants with BD-I (n = 24; 3 groups, 8 per group), 33% were male and 42% were white, with a mean of 13.0 years since diagnosis. Participants described numerous symptoms of their illnesses that impacted relationships and daily life, including effects on emotional health, the ability to work, and encounters with law enforcement. Previous antipsychotic medications were deemed effective by 14/15 (93%) participants with SZ and 12/16 (75%) participants with BD-I. Most participants with SZ (13/15; 87%) or with BD-I (16/24; 67%) reported discontinuing their antipsychotic medication at some point. Side effects were a common reason for discontinuing or switching medications for participants with SZ (8/15; 53%) and for those with BD-I (11/24; 46%). The most common side effects reported in both cohorts were weight gain, drowsiness, sexual problems, and neurologic symptoms. Side effects negatively affected quality of life, leading to serious health problems and issues with self-esteem. CONCLUSIONS: People living with SZ or BD-I cited a range of favourable and unfavourable experiences with oral antipsychotic medications. Most participants reported that their antipsychotics were effective at controlling their symptoms, but multiple side effects impacted their quality of life, caused additional serious health problems, and often led to discontinuation of or switching antipsychotics. Findings from this study contribute to a better understanding of patients' experiences with antipsychotics and highlight a need for new medications with favourable benefit/risk profiles.

The Acceptability of Remotely Delivered Cognitive Adaptation Training.

Cognitive Adaptation Training (CAT) is a psychosocial treatment using environmental supports such as signs, checklists, technology, and the organization of belongings to bypass cognitive and motivational impairments for those with serious behavioral health problems. We conducted a survey of 204 members of managed Medicaid in Texas to examine the acceptability of, opinions about and preferences for CAT delivered in-person (CAT) or remotely (R-CAT) where supplies would be mailed and visits would occur via videoconferencing. The telephone survey presented descriptions of CAT and R-CAT in counterbalanced order eliciting general opinions about the treatments, such as (1) whether they would accept the treatments if they were offered the day of the survey at no cost, (2) which treatment was preferred, and (3) the extent to which they agreed or disagreed with a number of statements about components of the treatments. Results indicated that both R-CAT and CAT were acceptable to respondents with overall acceptance rates significantly higher for R-CAT 87% than for CAT (78%). With respect to preferences, 27% and 28% of respondents preferred CAT and R-CAT, respectively, and 41% of respondents preferred both equally. Black respondents more often preferred in-person CAT to other alternatives. Respondents agreed that they needed help, that they were comfortable with technology, and that they believed the programs would help them. The vast majority of qualitative comments about the treatments were positive. Results suggest that it will be important to assess the efficacy and effectiveness of CAT delivered remotely in randomized trials.

In-office, in-home, and telehealth cognitive processing therapy for posttraumatic stress disorder in veterans: a randomized clinical trial.

BACKGROUND: Trauma-focused psychotherapies for combat-related posttraumatic stress disorder (PTSD) in military veterans are efficacious, but there are many barriers to receiving treatment. The objective of this study was to determine if cognitive processing therapy (CPT) for PTSD among active duty military personnel and veterans would result in increased acceptability, fewer dropouts, and better outcomes when delivered In-Home or by Telehealth as compared to In-Office treatment. METHODS: The trial used an equipoise-stratified randomization design in which participants (N = 120) could decline none or any 1 arm of the study and were then randomized equally to 1 of the remaining arms. Therapists delivered CPT in 12 sessions lasting 60-min each. Self-reported PTSD symptoms on the PTSD Checklist for DSM-5 (PCL-5) served as the primary outcome. RESULTS: Over half of the participants (57%) declined 1 treatment arm. Telehealth was the most acceptable and least often refused delivery format (17%), followed by In-Office (29%), and In-Home (54%); these differences were significant (p = 0.0008). Significant reductions in PTSD symptoms occurred with all treatment formats (p < .0001). Improvement on the PCL-5 was about twice as large in the In-Home (d = 2.1) and Telehealth (d = 2.0) formats than In-Office (d = 1.3); those differences were statistically large and significant (d = 0.8, 0.7 and p = 0.009, 0.014, respectively). There were no significant differences between In-Home and Telehealth outcomes (p = 0.77, d = -.08). Dropout from treatment was numerically lowest when therapy was delivered In-Home (25%) compared to Telehealth (34%) and In-Office (43%), but these differences were not statistically significant. CONCLUSIONS: CPT delivered by telehealth is an efficient and effective treatment modality for PTSD, especially considering in-person restrictions resulting from COVID-19. TRIAL REGISTRATION: ClinicalTrials.gov ID NCT02290847 (Registered 13/08/2014; First Posted Date 14/11/2014).

Perspectives of Patients and Providers in Using Shared Decision Making in Psychiatry.

There is increased interest over the last decade in the use of Shared Decision Making with individuals with serious mental illness to improve engagement in treatment and clinical outcomes. We conducted semi-structured qualitative interviews with 15 individuals with serious mental illness treated in an outpatient transitional care clinic serving people immediately after discharge from a psychiatric hospitalization. Parallel interviews were conducted with a variety of clinical providers (n = 9). Using latent thematic analysis, six themes were identified including: (1) Differences in the Use of SDM, (2) Consideration of Past Experiences, (3) Decisional Power Preferences, (4) Use of SDM in Psychiatry Versus Other Areas of Medicine, (5) Dignity and Disengagement, and (6) External Forces Impacting SDM. Implications for clinical practice and research using a shared decision-making approach within this treatment setting are further discussed.

Prescriber Attitudes, Experiences, and Proclivities Toward Digital Medicine and How They Influence Adoption of Digital Medicine Platforms.

BACKGROUND: Psychiatric prescribers (prescribers) typically assess medication adherence by patient or caregiver self-report. Despite likely clinical benefit of a new digital medicine technology, the role of specific prescriber attitudes, behaviors, and experiences in the likelihood of adoption is unclear. OBJECTIVE: To identify prescriber characteristics that may affect adoption of the ingestible event marker (IEM) platform. DESIGN: A survey of prescribers treating seriously mentally ill patients was conducted. Factor analysis was performed on 11 items representing prescriber characteristics believed to be related to endorsement of the IEM platform. Four factors were extracted. Regression analysis was used to test the strength of the relationships between the factors and likelihood of adoption of the IEM platform. RESULTS: A total of 131 prescribers completed the survey. Most (84%) agreed that visits allow enough time to monitor adherence. Factor analysis revealed four underlying dimensions: 1) perspectives on the value of adherence; 2) concerns about measuring adherence; 3) views toward digital health technologies; and 4) views on payer role/reimbursement. Factors 1 and 3 were related to gender, the belief that computerization benefits prescribers, the presence of office support staff, and the belief that new digital medicine (DM) technology will be cost prohibitive. Willingness to adopt the IEM platform was related to gender (p < 0.05) and perspectives on the value of adherence (p < 0.05), with those scoring higher on that measure also being more likely to adopt. CONCLUSION: Psychiatric prescribers are concerned about medication adherence, perceive current monitoring tools to be problematic, and are open to using digital technologies to improve accuracy of adherence assessment. Relationships among prescriber characteristics, beliefs, and experiences should be considered when developing educational materials, particularly when the goal is to encourage adoption and use of the IEM platform.

A Program to Increase the Appropriate Use of Long-Acting Injectable Antipsychotic Medications in Community Settings.

OBJECTIVE: The Multilevel Facilitation of Long-Acting Antipsychotic Medication Program (MAP) is a novel intervention to increase the appropriate use of long-acting injectable (LAI) antipsychotics in community mental health clinics. The authors investigated the feasibility of MAP, facilitators and barriers to use, and preliminary impact on LAI medication use. METHODS: Two clinics in Texas and two in Ohio serving 750 and 617 individuals with schizophrenia receiving oral antipsychotics, respectively, were asked to change clinical procedures for 1 year by using either the not receiving optimum benefit (NOB) checklist or the checklist plus MAP. Providers used the NOB checklist to identify individuals who could benefit from switching to LAI antipsychotics. MAP clinics used the NOB checklist plus nonbranded academic detailing for providers and a shared-decision-making video and tool for consumers. Use of MAP components was tracked, and barriers and facilitators were collected quarterly. Antipsychotic prescription counts were provided by participating clinics. RESULTS: Barriers to use of MAP included loss of local champions and administrators, difficulty with provider buy-in, limited availability of peer specialists, and a lack of infrastructural support to integrate MAP into clinic flow. Higher scores on the NOB checklist were associated with more provider LAI medication offers and greater patient acceptance of LAI antipsychotics. LAI medication use increased in clinics over time, but it is unclear whether this increase was due to MAP. CONCLUSIONS: Changing MAP components to fit local procedures and to circumvent unique barriers could aid implementation. Further research should investigate the potential impact of MAP components on LAI medication use.

Antipsychotic Treatment Experiences of People with Schizophrenia: Patient Perspectives from an Online Survey.

BACKGROUND: This survey examined the experiences of people living with schizophrenia who have used oral antipsychotics (APs). METHODS: Adults with self-reported physician-diagnosed schizophrenia (N=200), who were members of an online research participation panel and reported taking one or more oral APs within the last year, completed a cross-sectional online survey that focused on direct report of their experiences regarding APs (eg, symptoms, side effects, adherence). Descriptive analyses were conducted for the total survey sample and for subgroups defined a priori by experience with specific, prevalent side effects. RESULTS: The mean age of the sample was 41.9 (SD=11.0) years, 50% of participants were female, and 32% were nonwhite. Overall ratings were positive for medication effectiveness and convenience but negative for side effects. While most participants reported that APs improved schizophrenia symptoms (92%), 27% reported APs as having done "more harm than good." Almost all participants (98%) reported experiencing side effects of APs, with the most common being anxiety (88%), feeling drowsy/tired (86%), and trouble concentrating (85%). Side effects frequently cited as either "extremely" or "very" bothersome were weight gain (56%), sexual dysfunction (55%), and trouble concentrating (54%). Over 80% reported that side effects had negatively impacted their work and social functioning (eg, social activities or family/romantic relationships). Since initiating treatment, 56% of respondents had stopped taking APs at some point (65% of these due to side effects). Side effects commonly reported as having led to stopping AP treatment were "feeling like a 'zombie'" (22%), feeling drowsy/tired (21%), and weight gain (20%). CONCLUSION: Most participants reported improvements in schizophrenia symptoms associated with the use of APs. However, most participants also reported experiencing numerous bothersome side effects that negatively impacted their work, social functioning, and treatment adherence. Results highlight the unmet need for new APs with favorable benefit-risk profiles.

Antipsychotic treatment experiences of people with bipolar I disorder: patient perspectives from an online survey.

BACKGROUND: Oral antipsychotic (AP) medications are frequently prescribed to people with bipolar I disorder (BD-I). A cross-sectional online survey examined the experiences of people living with BD-I with a history of recent AP use. METHODS: Adults with self-reported physician-diagnosed BD-I (N = 200) who received oral APs during the prior year completed a survey on AP-related experiences, including side effects and their perceived burden on social functioning, adherence, and work. Items also assessed preferences for trade-offs (balancing symptom management and side effects) when considering a hypothetical new AP. The perceived impact of specific, prevalent side effects on adherence, work, and preferences for a hypothetical AP were also examined. Analyses were descriptive. RESULTS: The survey sample had a mean age of 43.2 (SD = 12.4) years, was 60% female, and 31% nonwhite. Almost all participants (98%) had experienced AP side effects. Common self-reported side effects were feeling drowsy or tired (83%), lack of emotion (79%), anxiety (79%), dry mouth (76%), and weight gain (76%). Weight gain was cited as the most bothersome side effect, rated by most participants (68%) as "very" or "extremely bothersome." Nearly half of participants (49%) reported that AP side effects negatively impacted their job performance; almost all (92%) reported that side effects - most commonly anxiety and lack of emotion - negatively impacted social relationships (e.g., family or romantic partners). The most commonly-reported reason for stopping AP use was dislike of side effects (48%). Side effects most likely to lead to stopping or taking less of AP treatment included "feeling like a 'zombie'" (29%), feeling drowsy or tired (25%), and weight gain (24%). When considering a hypothetical new AP, the most common side effects participants wanted to avoid included AP-induced anxiety (50%), weight gain (48%), and "feeling like a 'zombie'" (47%). CONCLUSIONS: Side effects of APs were both common and bothersome, and impacted social functioning, adherence, and work. Findings highlight the prevailing unmet need for new APs with more favorable benefit-risk profiles.

Facilitating Recovery of Daily Functioning in People With a Severe Mental Illness Who Need Longer-Term Intensive Psychiatric Services: Results From a Cluster Randomized Controlled Trial on Cognitive Adaptation Training Delivered by Nurses.

BACKGROUND: Feasible and effective interventions to improve daily functioning in people with a severe mental illness (SMI), such as schizophrenia, in need of longer-term rehabilitation are scarce. AIMS: We assessed the effectiveness of Cognitive Adaptation Training (CAT), a compensatory intervention to improve daily functioning, modified into a nursing intervention. METHOD: In this cluster randomized controlled trial, 12 nursing teams were randomized to CAT in addition to treatment as usual (CAT; n = 42) or TAU (n = 47). Daily functioning (primary outcome) was assessed every 3 months for 1 year. Additional follow-up assessments were performed for the CAT group in the second year. Secondary outcomes were assessed every 6 months. Data were analyzed using multilevel modeling. RESULTS: CAT participants improved significantly on daily functioning, executive functioning, and visual attention after 12 months compared to TAU. Improvements were maintained after 24 months. Improved executive functioning was related to improved daily functioning. Other secondary outcomes (quality of life, empowerment, negative symptoms) showed no significant effects. CONCLUSIONS: As a nursing intervention, CAT leads to maintained improvements in daily functioning, and may improve executive functioning and visual attention in people with SMI in need of longer-term intensive psychiatric care. Given the paucity of evidence-based interventions in this population, CAT can become a valuable addition to recovery-oriented care.

Assessment of adherence to oral antipsychotic medications: What has changed over the past decade?

INTRODUCTION: In a previous review, spanning 3 decades, we found that self-report and other non-objective measures were the primary means of assessing adherence to oral antipsychotic medications for individuals with schizophrenia. Moreover, consensus regarding the definition of adherence was completely lacking. Here, we examined the next decade of studies to determine what may have changed. METHOD: We searched the peer reviewed literature published between January 1, 2007 and December 31, 2017 using Google scholar, Science Direct, CINAHL, PsychINFO, PsychARTICLES and Medline. Search terms were medication adherence or medication compliance or medication acceptance or medication follow-through or medication concordance or medication persistence AND schizophrenia. We included articles that assessed adherence behavior. RESULTS: The search yielded 663 articles, 363 of these were eliminated. Included studies represent over 560,000 individuals. Definitions of adherence remain variable with cutoffs from 67% to 95%. Subjective measures of adherence remain the most commonly used. However, the use of objective measures has significantly increased, as has the use of electronic claims data. However, the absolute number of studies using objective measures remains low and very few approaches identify the amount of medication actually taken. CONCLUSIONS: Some movement toward more standardization and the use of more objective measures of adherence has been made over the past decade. However, objective measures continue to be underutilized and definitions remain variable. Assessing adherence in less than optimal ways calls into question the results of studies purporting to identify reasons for problem adherence and to elucidate the relationships among adherence and other variables.

Caregiver Burdens Associated With Treatment-Resistant Schizophrenia: A Quantitative Caregiver Survey of Experiences, Attitudes, and Perceptions.

Background: Previous qualitative studies indicate high caregiver burden associated with providing care for people with treatment-resistant schizophrenia (TRS). In this study, we report the first quantitative data to characterize the burdens of caring for a person living with TRS. To better understand the potential added burdens of persistent positive symptoms, we compared the self-reported burdens of caregiving for people living with TRS versus caregiving for those whose positive schizophrenia symptoms respond to treatment (comparator group). Methods: Non-professional adult caregivers providing ≥20 h/week of care to individuals with schizophrenia completed an online survey. Allocation to the TRS or comparator groups was based on caregiver report. TRS was defined as failure of ≥2 separate antipsychotics and at least moderate severity in two of four persistent core positive symptoms despite medication adherence. Care recipients in the comparator schizophrenia group had no clinically significant positive symptoms. Results: One hundred seventy seven caregivers (n = 100 TRS group, n = 77 comparator group) completed the online survey. Caregivers in both groups reported high levels of every day involvement in most aspects of daily life, including assistance with basic tasks, housekeeping, and in providing emotional support. There were no significant differences between groups on overall social life or health. However, caregivers of people living with TRS were significantly more likely to be experiencing stress (76% vs. 53%) and anxiety (58% vs. 43%). Relevant differences between caregiver groups were also noted for mean number of hours spent per week on direct care (TRS group vs. comparator group: 61.1 h/week vs. 39.7 h/week, respectively) and time spent "on call" (162.8 h/week vs. 121.6 h/week). Amongst the caregivers in the TRS group, correlation analyses revealed moderate positive correlations between the reported burden of individual persistent positive symptoms with overall caregiver burden. Conclusion: Our findings show that caring for a person living with TRS places considerable burden on caregivers' lives, with the severity of the disease (and especially severity of positive symptoms) driving further burden, as highlighted by a number of quantitative differences between the TRS and comparator groups.