Appropriate controls for digital therapeutic clinical trials: A narrative review of control conditions in clinical trials of digital therapeutics (DTx) deploying psychosocial, cognitive, or behavioral content.

Digital therapeutics (DTx) are software programs that treat a disease or condition. Increasingly, DTx are part of medical care, and in the US healthcare system they are regulated by the FDA as Software as a Medical Device (SaMD). Randomized controlled trials (RCT) remain a key evidence generation step for most DTx. However, developing a unified approach to the design of appropriate control conditions has been a challenge for two main reasons: (1) inheriting control condition definitions from pharmacotherapy and medical device RCT that may not directly apply, and (2) challenges in establishing control conditions for psychosocial interventions that build the core of many DTx. In our critical review we summarize different approaches to control conditions and patient blinding in RCT evaluating DTx with psychosocial, cognitive or behavioral content. We identify control condition choices, ranging from very minimal digital controls to more complex and stringent digital applications that contain aspects of "fake" therapy, general wellness content or games. Our review of RCTs reveals room for improvement in describing and naming control conditions more consistently. We further discuss challenges in defining placebo controls for DTx and ways in which control choices may have a therapeutic effect. While no one-size-fits-all control conditions and study designs will apply to all DTx, we propose points to consider for defining appropriate digital control conditions. At the same time, given the rapid iterative development and optimization of DTx, treatments with low risk profile may be evaluated with minimal digital controls followed by extensive real-world effectiveness trials.

What gets in the way of social engagement in schizophrenia?

BACKGROUND: Social engagement-important for health and well-being-can be difficult for people with schizophrenia. Past research indicates that despite expressing interest in social interactions, people with schizophrenia report spending less time with others and feeling lonely. Social motivations and barriers may play an important role for understanding social engagement in schizophrenia. AIM: To investigate how people with schizophrenia describe factors that impede and promote social engagement. METHODS: We interviewed a community sample of people with (n = 35) and without (n = 27) schizophrenia or schizoaffective disorder about their social interactions with friends and family over the past week and planned social activities for the coming week. We reviewed the interview transcripts and developed a novel coding system to capture whether interactions occurred, who had initiated the contact, and frequency of reported social barriers (i.e., internal, conflict-based, logistical) and social motivations (i.e., instrumental, affiliative, obligation-based). We also assessed symptoms and functioning. RESULTS: People with schizophrenia were less likely than people without schizophrenia to have spent time with friends [t (51.04) = 2.09, P = 0.042, d = 0.51)], but not family. People with schizophrenia reported more social barriers than people without schizophrenia [F (1, 60) = 10.55, P = 0.002, ηp2 = 0.15)] but did not differ in reported social motivations. Specifically, people with schizophrenia reported more internal [t (45.75) = 3.40, P = 0.001, d = 0.83)] and conflict-based [t (40.11) = 3.03, P = 0.004, d = 0.73)] barriers than people without schizophrenia. Social barriers and motivations were related to real-world social functioning for people with schizophrenia, such that more barriers were associated with more difficulty in close relationships (r = -0.37, P = 0.027) and more motivations were associated with better community functioning (r = 0.38, P = 0.024). CONCLUSION: These findings highlight the importance of assessing first person accounts of social barriers and motivations to better understand social engagement in schizophrenia.

Oxytocin does not improve emotional prosody recognition in schizophrenia-spectrum disorders.

Schizophrenia-spectrum disorders (SSD) are associated with deficits in emotional prosody recognition. Whether administration of oxytocin can improve emotional prosody recognition accuracy in SSD is unknown. Sixty individuals with SSD and ninety-seven controls completed a placebo-controlled, double-blind, cross-over trial examining the effects of oxytocin on emotional prosody recognition accuracy. Compared to controls, SSD was associated with poorer emotional prosody recognition accuracy, regardless of stimulus valence or intensity, suggesting a generalized deficit. Oxytocin had no effect on emotional prosody recognition in either group, which is consistent with previous work suggesting that oxytocin only improves high-level social cognition in SSD.

A positive emotion regulation intervention for bipolar I disorder: Treatment development and initial outcomes.

OBJECTIVE: Dysfunction in positive affect is a defining symptom of bipolar I disorder (BD), both during and between mood episodes. We hypothesize that helping people with BD learn skills to create balance in their affective experiences by engaging in strategies that increase low activation positive emotion (LAP; e.g., relaxation) could help to improve well-being during periods of symptom remission. We discuss the development and preliminary outcomes of a positive emotion regulation (PER) group treatment for people with BD, designed as a supplement to pharmacological treatment. METHOD: The Learning Affective Understanding for a Rich Emotional Life (LAUREL) intervention is a group-based intervention covering 10 empirically supported skills designed to increase LAP. Sixteen people with BD enrolled in the LAUREL intervention and twelve completed baseline and post-intervention assessments. RESULTS: Participants who completed the study (n = 12) attended the majority of groups (87.96%) and reported practicing skills, on average, 16 times a week. We were unable to detect significant differences in mania symptoms following engagement in this PER intervention. Finally, participants reported increases in several areas associated with well-being post-intervention, including mindfulness, reappraisal, and self-compassion. CONCLUSION: This study provides a theoretical framework and preliminary support for a PER intervention for BD.

Defeatist performance beliefs in college students: Transdiagnostic associations with symptoms and daily goal-directed behavior.

Defeatist performance beliefs are prevalent and linked to decreased motivation in people with psychological disorders. In this study, we investigated whether defeatist performance beliefs were associated with transdiagnostic psychopathology risk in people with no history of formal diagnosis and whether defeatist performance beliefs impacted engagement in daily goal-directed behavior. One hundred and two college students completed self-report measures of defeatist performance beliefs and risk for depression, mania, and psychosis. Sixty-one of these participants were randomly selected to identify a goal and complete daily surveys about their actual and expected goal progress, effort expenditure, experienced pleasure, and difficulty of goal pursuit. We found that greater defeatist performance beliefs were associated with higher risk for depression, mania, and psychosis. Using multilevel modeling, we found that greater defeatist performance beliefs predicted less goal progress, effort expenditure, and pleasure from goal pursuit. Together, these findings suggest that defeatist performance beliefs may impact goal-directed behavior in healthy people with no reported psychiatric history. Interventions targeting defeatist performance beliefs may have utility for actual goal-directed behavior in many people, regardless of psychiatric status.

Efficacy of PRIME, a Mobile App Intervention Designed to Improve Motivation in Young People With Schizophrenia.

The onset of schizophrenia occurs during a period critical for development of social relationships and functional independence. As such, interventions that target the early course of illness have the potential to stave off functional decline and restore functioning to pre-illness levels. In this entirely remote study, people with recent-onset schizophrenia spectrum disorders (SSDs) participated in a 12-week randomized controlled trial to determine the efficacy of PRIME (personalized real-time intervention for motivational enhancement), a mobile-based digital health intervention designed to improve motivation and quality of life. Participants were randomized into the PRIME (n = 22) or treatment-as-usual/waitlist (TAU/WL) condition (n = 21) and completed assessments at baseline, post-trial (12 wk), and for people in the PRIME condition, 3 months after the end of the trial. After 12-weeks, WL participants received PRIME, resulting in a total sample of 38 participants completing PRIME. In PRIME, participants worked towards self-identified goals with the support of a virtual community of age-matched peers with schizophrenia-spectrum disorders as well as motivation coaches. Compared to the WL condition, people in the PRIME condition had significantly greater improvements in self-reported depression, defeatist beliefs, self-efficacy, and a trend towards motivation/pleasure negative symptoms post-trial, and these improvements were maintained 3 months after the end of trial. We also found that people in the PRIME condition had significantly greater improvements in components of social motivation post-trial (anticipated pleasure and effort expenditure). Our results suggest that PRIME has the potential to be an effective mobile-based intervention for improving aspects of mood and motivation in young people with SSDs.

Parsing positivity in the bipolar spectrum: The effect of context on social decision-making.

INTRODUCTION: People with bipolar disorder often show more approach-related behavior and positive appraisals of others during social interactions. This may be due to an increased sensitivity to positive contexts or to tendencies toward positive affectivity. In this study, we investigated the influence of reward versus prosocial positive contexts on social decision-making in people at high (n = 21) and low (n = 111) risk for bipolar disorder. METHODS: Participants completed a computerized task consisting of two blocks. In the No Context block, participants were presented with a face and asked to make decisions related to approach, appraisal, and trust behavior toward that person. In the Context block, designed to assess the influence of contextual information on decision-making, each face was preceded by a written statement describing a positive or neutral context. RESULTS: Compared to the low risk group, the high-risk group made significantly higher approach and appraisal ratings, regardless of the context condition. Effects were sustained controlling for positive affect. We did not find any effect of bipolar risk on trust ratings. LIMITATIONS: The study was conducted in an analogue sample. DISCUSSION: Taken together, these results suggest risk for bipolar disorder is associated with greater positive social approach and appraisal tendencies, and that these effects are not secondary to social context or positive affect. Implications for understanding social decision-making in the bipolar spectrum are discussed.

Social motivation in people with recent-onset schizophrenia spectrum disorders.

People with schizophrenia-spectrum disorders (SSD) often experience impairments in non-social motivation. In this study, we extended this line of investigation by examining specific components of social motivation and the extent to which these components work together in people with and without a recent-onset SSD. Sixty-four people with a recent-onset SSD and 26 controls completed a task that allowed us to examine changes in anticipated pleasure, decisions to trust, and effort expenditure over the course of repeated interactions with positive or negative outcomes. Compared to controls, we found that people in the SSD group placed less trust, tended to anticipate less pleasure, and expended less effort to increase the likelihood of future interactions with positive outcomes. Further, in the SSD group, effort expenditure was not associated with either anticipated pleasure or decisions to trust. While there were no group differences in anticipated pleasure or trust placed during interactions with negative outcomes, people in the SSD group expended less effort to decrease to the likelihood of future interactions. Taken together, our findings suggest that people with a recent-onset SSD may experience both impairment and disconnection between various components of social motivation for interactions with positive outcomes. Implications for interventions for social engagement in people with SSD are discussed.

Anticipated pleasure for positive and negative social interaction outcomes in schizophrenia.

While recent research suggests that people with schizophrenia anticipate less pleasure for non-social events, considerably less is known about anticipated pleasure for social events. In this study, we investigated whether people with and without schizophrenia differ in the amount and updating of anticipated pleasure over the course of repeated interactions as well as the influence of emotional displays. Thirty-two people with schizophrenia and 29 controls rated their anticipated pleasure over the course of repeated interactions with smiling, scowling, or neutral social partners that had either positive or negative outcomes. Compared to controls, people with schizophrenia anticipated a lower amount of pleasure during interactions with smiling, but not neutral social partners that had positive outcomes. However, the groups did not differ in the amount or updating of anticipated pleasure during interactions that had negative outcomes. Both groups anticipated more pleasure over the course of repeated interactions with smiling partners and less pleasure over the course of repeated interactions with scowling partners compared to interactions with neutral partners. We discuss how less anticipated pleasure for interactions with smiling social partners may be linked to difficulties in social engagement among people with schizophrenia.

High inpatient utilization among Veterans Health Administration patients with substance-use disorders and co-occurring mental health conditions.

BACKGROUND: Substance-use disorders (SUDs) are common and costly conditions. Understanding high inpatient utilization (HIU) among patients with SUD can inform the development of treatment approaches designed to reduce healthcare expenditures and improve service quality. OBJECTIVES: To examine the prevalence, type, and predictors of HIU among patients with SUD and co-occurring mental health conditions. METHODS: Service utilization and demographic and clinical variables were extracted from a national sample of Veterans Health Administration (VA) patients with SUD-only [n = 148,960 (98.3% male)], SUD plus serious mental illness ([i.e. schizophrenia- and/or bipolar-spectrum disorders; SUD/SMI; n = 75,913 (91.6% male)], and SUD plus other mental illness [SUD/MI; n = 245,675 (94.6% male)]. Regression models were used to examine HIU during a follow-up year. RESULTS: Prevalence of HIU among the SUD-only group was 6.2% (95% confidence interval (CI): 6.1%-6.3%) compared with 22.7% (95% CI: 22.4%-23.0%) and 9.7% (95% CI: 9.6%-9.8%) among the SUD/SMI and SUD/MI groups, respectively. Patients with SUD/MI represented nearly half of the HIU sample. Primary type of inpatient service use varied by comorbidity: SUD-only = medicine; SUD/SMI = psychiatric; SUD/MI similar use of psychiatric, SUD-related, and medicine. Predictors of HIU were generally similar across groups: older age, unmarried, homelessness, suicide risk, pain diagnosis, alcohol/opioid/sedative-use disorders, and prior-year emergency department/inpatient utilization. CONCLUSIONS: Substantial reductions in HIU among an SUD population will likely require treatment approaches that target patients with less-severe mental health conditions in addition to SMI. Cross-service collaborations (e.g., integration of medical providers in SUD care) and interventions designed to target issues and/or conditions that lead to HIU (e.g., homeless care services) may be critical to reducing HIU in this population.

The feasibility, acceptability, and outcomes of PRIME-D: A novel mobile intervention treatment for depression.

BACKGROUND: Despite decades of research and development, depression has risen from the fifth to the leading cause of disability in the United States. Barriers to progress in the field are (1) poor access to high-quality care; (2) limited mental health workforce; and (3) few providers trained in the delivery of evidence-based treatments (EBTs). Although mobile platforms are being developed to give consumers greater access to high-quality care, too often these tools do not have empirical support for their effectiveness. In this study, we evaluated PRIME-D, a mobile app intervention that uses social networking, goal setting, and a mental health coach to deliver text-based, EBT's to treat mood symptoms and functioning in adults with depression. METHODS: Thirty-six adults with depression remotely participated in PRIME-D over an 8-week period with a 4-week follow-up, with 83% retained over the 12-week course of thestudy. RESULTS: On average, participants logged into the app 5 days/week. Depression scores (PHQ-9) significantly improved over time (over 50% reduction), with coach interactions enhancing these effects. Mood-related disability (Sheehan Disability Scale (SDS)) also significantly decreased over time with participants no longer being impaired by their mood symptoms. Overall use of PRIME-D predicted greater gains in functioning. Improvements in mood and functioning were sustained over the 4-week follow-up. CONCLUSIONS: Results suggest that PRIME-D is a feasible, acceptable, and effective intervention for adults with depression and that a mobile service delivery model may address the serious public health problem of poor access to high-quality mental health care.

Negative symptoms in psychometrically defined schizotypy: The role of depressive symptoms.

People high in schizotypy, a risk factor for schizophrenia-spectrum disorders, can have negative symptoms, including diminished experience of motivation/pleasure (MAP) and emotional expressivity (EXP). Additionally, people high in schizotypy often report elevated depressive symptoms, which are also associated with diminished MAP and EXP. In this study, we examined whether negative symptoms were related to schizotypy above and beyond the presence of depressive symptoms. Thirty-one people high in schizotypy and 24 people low in schizotypy were administered the Clinical Assessment Interview for Negative Symptoms (CAINS), an interview-based measure of MAP and EXP negative symptoms and completed a self-report measure of cognitive and somatic-affective depressive symptoms. People high in schizotypy had more MAP negative symptoms than people low in schizotypy, but we found no group differences in EXP negative symptoms. Importantly, the relationship between MAP negative symptoms and schizotypy was fully mediated by cognitive depressive symptoms. These findings suggest that depressive symptoms, specifically cognitive depressive symptoms, may be a pathway for motivation and pleasure impairment, in people at elevated risk for developing schizophrenia-spectrum disorders.

Defeatist Performance Beliefs, Negative Symptoms, and Functional Outcome in Schizophrenia: A Meta-analytic Review.

Negative symptoms are a strong predictor of poor functional outcome in people with schizophrenia. Unfortunately there are few effective interventions for either negative symptoms or functional outcome, despite the identification of potential mechanisms. Recent research, however, has elucidated a new potential mechanism for negative symptoms and poor functional outcome: defeatist performance beliefs (DPB), or negative thoughts about one's ability to successfully perform goal-directed behavior that can prevent behavior initiation and engagement. We conducted 2 meta-analyses examining the relationship between DPB and both negative symptoms (n = 10 studies) and functional outcome (n = 8 studies) in people with schizophrenia. We found a small effect size for the relationship between DPB and negative symptoms, regardless of how negative symptoms were measured. We also found a small effect size for the relationship between DPB and functional outcome, which was significantly moderated by the method of assessing DPB and moderated by the sex composition of the study at a trend level. These findings highlight the potential of targeting DPB in psychosocial interventions for both negative symptoms and functional outcome.

Using social outcomes to inform decision-making in schizophrenia: Relationships with symptoms and functioning.

The outcomes of the decisions we make can be used to inform subsequent choices and behavior. We investigated whether and how people with and without schizophrenia use positive and negative social outcomes and emotional displays to inform decisions to place trust in social partners. We also investigated the impact of reversals in social partners' behavior on decisions to trust. Thirty-two people with schizophrenia and 29 control participants completed a task in which they decided how much trust to place in social partners' showing either a dynamic emotional (smiling, scowling) or neutral display. Interactions were predetermined to result in positive (trust reciprocated) or negative (trust abused) outcomes, and we modeled changes in trust decisions over the course of repeated interactions. Compared to controls, people with schizophrenia were less sensitive to positive social outcomes in that they placed less trust in trustworthy social partners during initial interactions. By contrast, people with schizophrenia were more sensitive to negative social outcomes during initial interactions with untrustworthy social partners, placing less trust in these partners compared to controls. People with schizophrenia did not differ from controls in detecting social partner behavior reversals from trustworthy to untrustworthy; however, they had difficulties detecting reversals from untrustworthy to trustworthy. Importantly, decisions to trust were associated with real-world social functioning. We discuss the implications of these findings for understanding social engagement among people with schizophrenia and the development of psychosocial interventions for social functioning.

Modeling the role of negative symptoms in determining social functioning in individuals at clinical high risk of psychosis.

A priority for improving outcome in individuals at clinical high risk (CHR) is enhancing our understanding of predictors of psychosis as well as psychosocial functioning. Social functioning, in particular, is a unique indicator of risk as well as an important outcome in itself. Negative symptoms are a significant determinant of social functioning in CHR individuals; yet, it is unclear which specific negative symptoms drive functional outcome and how these symptoms function relative to other predictors, such as neurocognition and mood/anxiety symptoms. In a sample of 85 CHR individuals, we examined whether a two-factor negative symptom structure that is found in schizophrenia (experiential vs expressive symptoms) would be replicated in a CHR sample; and tested the degree to which specific negative symptoms predict social functioning, relative to neurocognition and mood/anxiety symptoms, which are known to predict functioning. The two-factor negative symptom solution was replicated in this CHR sample. Negative symptom severity was found to be uniquely predictive of social functioning, above and beyond depression/anxiety and neurocognition. Experiential symptoms were more strongly associated with social functioning, relative to expression symptoms. In addition, experiential symptoms mediated the relationship between expressive negative symptoms and social functioning. These results suggest that experiences of motivational impairment are more important in determining social functioning, relative to affective flattening and alogia, in CHR individuals, thereby informing the development of more precise therapeutic targets. Developing novel interventions that stimulate goal-directed behavior and reinforce rewarding experiences in social contexts are recommended.

The power to resist: the relationship between power, stigma, and negative symptoms in schizophrenia.

Stigmatizing beliefs about mental illness can be a daily struggle for people with schizophrenia. While investigations into the impact of internalizing stigma on negative symptoms have yielded mixed results, resistance to stigmatizing beliefs has received little attention. In this study, we examined the linkage between internalized stigma, stigma resistance, negative symptoms, and social power, or perceived ability to influence others during social interactions among people with schizophrenia. Further, we sought to determine whether resistance to stigma would be bolstered by social power, with greater power in relationships with other possibly buffering against motivation/pleasure negative symptoms. Fifty-one people with schizophrenia or schizoaffective disorder completed measures of social power, internalized stigma, and stigma resistance. Negative symptoms were assessed using the Clinical Assessment Interview for Negative Symptoms (CAINS). Greater social power was associated with less internalized stigma and negative symptoms as well as more stigma resistance. Further, the relationship between social power and negative symptoms was partially mediated by stigma resistance. These findings provide evidence for the role of stigma resistance as a viable target for psychosocial interventions aimed at improving motivation and social power in people with schizophrenia.

Who do you trust? The impact of facial emotion and behaviour on decision making.

During social interactions, we use available information to guide our decisions, including behaviour and emotional displays. In some situations, behaviour and emotional displays may be incongruent, complicating decision making. This study had two main aims: first, to investigate the independent contributions of behaviour and facial displays of emotion on decisions to trust, and, second, to examine what happens when the information being signalled by a facial display is incongruent with behaviour. Participants played a modified version of the Trust Game in which they learned simulated players' behaviour with or without concurrent displays of facial emotion. Results indicated that displays of anger, but not happiness, influenced decisions to trust during initial encounters. Over the course of repeated interactions, however, emotional displays consistent with an established pattern of behaviour made independent contributions to decision making, strengthening decisions to trust. When facial display and behaviour were incongruent, participants used current behaviour to inform decision making.