Assessing the Efficacy and Safety of a Digital Therapeutic for Symptoms of Depression in Adolescents: Protocol for a Randomized Controlled Trial.

BACKGROUND: Depression is a serious, prevalent, recurrent, and undertreated disorder in adolescents. Low levels of treatment seeking and treatment adherence in this age group, combined with a growing national crisis in access to mental health care, have increased efforts to identify effective treatment alternatives for this demographic. Digital health interventions for mental illness can provide cost-effective, engaging, and accessible means of delivering psychotherapy to adolescents. OBJECTIVE: This protocol describes a virtual randomized controlled trial designed to evaluate the efficacy and safety of a self-guided, mobile app-based implementation of behavioral activation therapy, SparkRx, for the adjunct treatment of symptoms of depression in adolescents. METHODS: Participants are recruited directly through web-based and print advertisements. Following eligibility screening and consenting, participants are randomly assigned to a treatment arm (SparkRx) or a control arm (assessment-enhanced usual care) for 5 weeks. The primary efficacy outcome, total score on the 8-item Patient Health Questionnaire (PHQ-8), is assessed at the end of the 5-week intervention period. Additional participant-reported outcomes are assessed at baseline, the postintervention time point, and 1-month follow-up. The safety of the intervention is assessed by participant report (and legal guardian report, if the participant is younger than 18 years) and by patterns of symptom deterioration on the PHQ-8, as part of a larger clinical safety monitoring protocol. The primary efficacy outcome, total PHQ-8 score at the postintervention time point, will be compared between SparkRx and enhanced usual care arms using mixed effect modeling, with baseline PHQ-8 and current antidepressant medication status included as covariates. Secondary efficacy outcomes, including the proportion of participants exhibiting treatment response, remission, and minimal clinically significant improvement (all derived from total PHQ-8 scores), will be compared between groups using chi-square tests. Symptom severity at 1-month follow-up will also be compared between arms. Planned subgroup analyses will examine the robustness of treatment effects to differences in baseline symptom severity (PHQ-8 score <15 or ≥ 15) and age (younger than 18 years and older than 18 years). The primary safety outcome, the number of psychiatric serious adverse events, will be compared between trial arms using the Fisher exact test. All other adverse events will be presented descriptively. RESULTS: As of May 2023, enrollment into the study has concluded; 223 participants were randomized. The analysis of the efficacy and safety data is expected to be completed by Fall 2023. CONCLUSIONS: We hypothesize that the results of this trial will support the efficacy and safety of SparkRx in attenuating symptoms of depression in adolescents. Positive results would more broadly support the prospect of using accessible, scientifically validated, digital therapeutics in the adjunct treatment of mental health disorders in this age range. TRIAL REGISTRATION: ClinicalTrials.gov NCT05462652; https://clinicaltrials.gov/study/NCT05462652. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/48740.

A CBT-based mobile intervention as an adjunct treatment for adolescents with symptoms of depression: a virtual randomized controlled feasibility trial.

Background: High rates of adolescent depression demand for more effective, accessible treatment options. A virtual randomized controlled trial was used to assess the feasibility and acceptability of a 5-week, self-guided, cognitive behavioral therapy (CBT)-based mobile application, Spark, compared to a psychoeducational mobile application (Active Control) as an adjunct treatment for adolescents with depression during the COVID-19 pandemic. Methods: A community sample aged 13-21, with self-reported symptoms of depression, was recruited nationwide. Participants were randomly assigned to use either Spark or Active Control (NSpark = 35; NActive Control = 25). Questionnaires, including the PHQ-8 measuring depression symptoms, completed before, during, and immediately following completion of the intervention, evaluated depressive symptoms, usability, engagement, and participant safety. App engagement data were also analyzed. Results: 60 eligible adolescents (female = 47) were enrolled in 2 months. 35.6% of those expressing interest were consented and all enrolled. Study retention was high (85%). Spark users rated the app as usable (System Usability Scalemean = 80.67) and engaging (User Engagement Scale-Short Formmean = 3.62). Median daily use was 29%, and 23% completed all levels. There was a significant negative relationship between behavioral activations completed and change in PHQ-8. Efficacy analyses revealed a significant main effect of time, F = 40.60, p < .001, associated with decreased PHQ-8 scores over time. There was no significant Group × Time interaction (F = 0.13, p = .72) though the numeric decrease in PHQ-8 was greater for Spark (4.69 vs. 3.56). No serious adverse events or adverse device effects were reported for Spark users. Two serious adverse events reported in the Active Control group were addressed per our safety protocol. Conclusion: Recruitment, enrollment, and retention rates demonstrated study feasibility by being comparable or better than other mental health apps. Spark was highly acceptable relative to published norms. The study's novel safety protocol efficiently detected and managed adverse events. The lack of significant difference in depression symptom reduction between Spark and Active Control may be explained by study design and study design factors. Procedures established during this feasibility study will be leveraged for subsequent powered clinical trials evaluating app efficacy and safety. Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT04524598.

Meaningful engagement: A crossfunctional framework for digital therapeutics.

Digital mental health interventions, or digital therapeutics, have the potential to transform the field of mental health. They provide the opportunity for increased accessibility, reduced stigma, and daily integration with patient's lives. However, as the burgeoning field continues to expand, there is a growing concern regarding the level and type of engagement users have with these technologies. Unlike many traditional technology products that have optimized their user experience to maximize the amount of time users spend within the product, such engagement within a digital therapeutic is not sufficient if users are not experiencing an improvement in clinical outcomes. In fact, a primary challenge within digital therapeutics is user engagement. Digital therapeutics are only effective if users sufficiently engage with them and, we argue, only if users meaningfully engage with the product. Therefore, we propose a 4-step framework to assess meaningful engagement within digital therapeutics: (1) Define the measure of value (2) Operationalize meaningful engagement for your digital therapeutic (3) Implement solutions to increase meaningful engagement (4) Iteratively evaluate the solution's impact on meaningful engagement and clinical outcomes. We provide recommendations to the common challenges associated with each step. We specifically emphasize a cross-functional approach to assessing meaningful engagement and use an adolescent-focused example throughout to further highlight developmental considerations one should consider depending on their target users.

An examination of an enhancing effect of music on attentional abilities in older persons with mild cognitive impairment.

While the effect of listening to music on cognitive abilities is highly debated, studies reporting an enhancing effect of music in elderly populations appear to be more consistent. In this study, the effects of listening to music on attention in groups of cognitively normal older adults and those with mild cognitive impairment were considered. Participants were exposed to both a music and silence condition, and after each condition performed Digit Span and Coding tasks which require attention for maximal performance. The hypothesis that listening to music, compared to a silence condition, enhances performance was not supported for either group. Various explanations for these findings are considered.

Reward anticipation and punishment anticipation are instantiated in the brain via opponent mechanisms.

fMRI investigations have examined the extent to which reward and punishment motivation are associated with common or opponent neural systems, but such investigations have been limited by confounding variables and methodological constraints. The present study aimed to address limitations of earlier approaches and more comprehensively evaluate the extent to which neural activation associated with reward and punishment motivation reflects opponent or shared systems. Participants completed a modified monetary incentive delay task, which involved the presentation of a cue followed by a target to which participants were required to make a speeded button press. Using a factorial design, cues indicated whether monetary reward and/or loss (i.e., cues signaled probability of reward, punishment, both, or neither) could be expected depending upon response speed. Neural analyses evaluated evidence of (a) directionally opposing effects by testing for regions of differential activation for reward and punishment anticipation, (b) mutual inhibition by testing for interactive effects of reward and punishment anticipation within a factorial design, and (c) opposing effects on shared outputs via a psychophysiological interaction analysis. Evidence supporting all three criteria for opponent systems was obtained. Collectively, present findings support conceptualizing reward and punishment motivation as opponent forces influencing brain and behavior and indicate that shared activation does not suggest the operation of a common neural mechanism instantiating reward and punishment motivation.

Rapid neuroendocrine responses to auditory courtship signals.

In many species, courtship signals enhance reproductive function in the receiver. How these social signals are processed by the brain, particularly how they induce an endocrine response, is not well understood. Songbirds provide an ideal model in which to study this phenomenon because of the large existing literature on both their auditory neurobiology and the control of their reproductive physiology by environmental cues. To date, all of the relevant studies on songbirds have involved measuring the effects of male vocalizations on ovarian function over a period of weeks, a time course that precludes detailed analysis of the neuroendocrine mechanisms operating during song perception. We played recordings of conspecific male song to laboratory-housed female white-throated sparrows and quantified the resulting rapid changes in LH as well as the induction of the immediate early gene Egr-1 in the GnRH system and mediobasal hypothalamus (MBH). Hearing song for 42 min induced LH release and Egr-1 expression in the MBH, but did not alter Egr-1 expression in GnRH neurons. The time course of LH release and the pattern of Egr-1 expression together suggest that song acts as a trigger to induce GnRH release in a manner resembling photostimulation. The Egr-1 response in the MBH was qualitatively distinguishable from the responses to either photostimulation or pharmacologically induced LH release but seemed to involve overlapping neuronal populations. Song-induced Egr-1 expression in the MBH was correlated with the expression in midbrain and forebrain auditory centers, further supporting a role for the MBH in processing social information.

Misunderstanding RDoC.

Mental illness is fundamentally mental, by definition about psychological rather than biological phenomena, but biological phenomena play key roles in understanding, preventing, and treating mental illness. The Research Domain Criteria initiative (RDoC) of the US National Institute of Mental Health is an unusually ambitious effort to foster integration of psychological and biological science in the service of psychopathology research. Some key features and common misunderstandings of RDoC are discussed here.

Recent advances in understanding emotion-driven temporal distortions.

Emotions are powerful drivers of distortions in time perception. Recent work continues to support arousal and attentional mechanisms of emotion-driven temporal distortions. A possible memory-related mechanism and various modulatory factors, such as age, gender, and psychopathology, have also been implicated in such distortions. Beyond the rich behavioral literature on this topic, neurobiological substrates associated with emotion-driven temporal distortions have begun to be identified and represent an important next step for research within this domain. The study of emotion-driven temporal distortions holds great promise for advancing our understanding of this perceptual phenomenon and how it may play a functional role in mediating changes in cognition, behavior, and emotion.

Emotional modulation of interval timing and time perception.

Like other senses, our perception of time is not veridical, but rather, is modulated by changes in environmental context. Anecdotal experiences suggest that emotions can be powerful modulators of time perception; nevertheless, the functional and neural mechanisms underlying emotion-induced temporal distortions remain unclear. Widely accepted pacemaker-accumulator models of time perception suggest that changes in arousal and attention have unique influences on temporal judgments and contribute to emotional distortions of time perception. However, such models conflict with current views of arousal and attention suggesting that current models of time perception do not adequately explain the variability in emotion-induced temporal distortions. Instead, findings provide support for a new perspective of emotion-induced temporal distortions that emphasizes both the unique and interactive influences of arousal and attention on time perception over time. Using this framework, we discuss plausible functional and neural mechanisms of emotion-induced temporal distortions and how these temporal distortions may have important implications for our understanding of how emotions modulate our perceptual experiences in service of adaptive responding to biologically relevant stimuli.

Discriminative Fear Learners are Resilient to Temporal Distortions during Threat Anticipation.

Discriminative fear conditioning requires learning to dissociate between safety cues and cues that predict negative outcomes yet little is known about what processes contribute to discriminative fear learning. According to attentional models of time perception, processes that distract from timing result in temporal underestimation. If discriminative fear learning only requires learning what cues predict what outcomes, and threatening stimuli distract attention from timing, then better discriminative fear learning should predict greater temporal distortion on threat trials. Alternatively, if discriminative fear learning also reflects a more accurate perceptual experience of time in threatening contexts, discriminative fear learning scores would predict less temporal distortion on threat trials, as time is perceived more veridically. Healthy young adults completed discriminative fear conditioning in which they learned to associate one stimulus (CS+) with aversive electrical stimulation and another stimulus (CS-) with non-aversive tactile stimulation and then an ordinal comparison timing task during which CSs were presented as task-irrelevant distractors Consistent with predictions, we found an overall temporal underestimation bias on CS+ relative to CS- trials. Differential skin conductance responses to the CS+ versus the CS- during conditioning served as a physiological index of discriminative fear conditioning and this measure predicted the magnitude of the underestimation bias, such that individuals exhibiting greater discriminative fear conditioning showed less underestimation on CS+ versus CS- trials. These results are discussed with respect to the nature of discriminative fear learning and the relationship between temporal distortions and maladaptive threat processing in anxiety.

Hear it playing low and slow: how pitch level differentially influences time perception.

Variations in both pitch and time are important in conveying meaning through speech and music, however, research is scant on perceptual interactions between these two domains. Using an ordinal comparison procedure, we explored how different pitch levels of flanker tones influenced the perceived duration of empty interstimulus intervals (ISIs). Participants heard monotonic, isochronous tone sequences (ISIs of 300, 600, or 1200 ms) composed of either one or five standard ISIs flanked by 500 Hz tones, followed by a final interval (FI) flanked by tones of either the same (500 Hz), higher (625 Hz), or lower (400 Hz) pitch. The FI varied in duration around the standard ISI duration. Participants were asked to determine if the FI was longer or shorter in duration than the preceding intervals. We found that an increase in FI flanker tone pitch level led to the underestimation of FI durations while a decrease in FI flanker tone pitch led to the overestimation of FI durations. The magnitude of these pitch-level effects decreased as the duration of the standard interval was increased, suggesting that the effect was driven by differences in mode-switch latencies to start/stop timing. Temporal context (One vs. Five Standard ISIs) did not have a consistent effect on performance. We propose that the interaction between pitch and time may have important consequences in understanding the ways in which meaning and emotion are communicated.

Differential effects of amphetamine and haloperidol on temporal reproduction: dopaminergic regulation of attention and clock speed.

Healthy volunteers were tested on 7-s and 17-s peak-interval timing procedures following d-amphetamine (20mg-oral), haloperidol (2mg-oral), and placebo treatments in order to assess the dopaminergic regulation of temporal processing. Individual differences were observed in the drug effects such that two different patterns of timing behavior emerged. In the first pattern, d-amphetamine produced proportional leftward shifts of the timing functions while haloperidol produced proportional rightward shifts. This symmetrical pattern of results suggests that clock speed is regulated by the effective level of dopamine, i.e., d-amphetamine increases clock speed and haloperidol decreases clock speed. The second pattern was the opposite of the first pattern and was revealed by d-amphetamine producing proportional rightward shifts of the timing functions while haloperidol produced no reliable effect. This asymmetrical pattern of results is consistent with an explanation in which attention toward the stimulant-induced euphoria produced by d-amphetamine diminishes the attentional resources available for temporal processing, thereby diluting any drug-induced changes in clock speed. The result of increased competition and time-sharing between these two dimensions (e.g., attention towards feelings of euphoria versus attention towards the passage of time) leads to the underestimation/overproduction of temporal intervals. Interestingly, participants that displayed the 'clock-speed' pattern liked d-amphetamine significantly less than participants that displayed the 'attention' pattern and were more variable in a simple reaction time task than other participants. These results suggest that individuals with a higher degree of sensitivity to time are also more sensitive to their feelings of stimulant-induced euphoria and drug liking-suggesting that internal clock and reward pathways share common dopaminergic pathways.

Activity of the hypothalamic-pituitary-gonadal axis differs between behavioral phenotypes in female white-throated sparrows (Zonotrichia albicollis).

The white-throated sparrow (Zonotrichia albicollis) lends itself particularly well to investigations of neuroendocrine mechanisms of social behavior because of a behavioral polymorphism that correlates with a plumage phenotype. Roughly half of the individuals of this species exhibit a white stripe (WS) on the crown and engage in a more aggressive strategy, whereas the other half exhibit a tan stripe (TS) and assume a more parental strategy. These behavioral differences are mirrored by hormonal and neuroendocrine differences; for example, males of the WS morph have higher plasma testosterone than do TS males, and females of the TS morph have higher plasma luteinizing hormone than females of the WS morph. These differences suggest that the regulation of the hypothalamic-pituitary-gonadal (HPG) axis may differ according to morph. In this study, we compared HPG axis activity at each level by measuring (1) the number, size, and staining intensity of GnRH immunoreactive (ir) neurons; (2) plasma LH; and (3) plasma estradiol (E2) in females. We found that TS females had more GnRH-ir neurons in the septo-preoptic area of the hypothalamus than did WS females, and GnRH-ir neuronal cell bodies were larger in the WS than the TS females. There was no morph difference in the intensity of GnRH labeling. TS females had higher plasma LH, which is consistent with a previous report, and higher plasma E2. We hypothesize that the differences in GnRH-ir cell number and size are related to differences in LH and E2 secretion, and may be relevant to polymorphic social behavior.