Optimizing Outcomes in Psychotherapy for Anxiety Disorders Using Smartphone-Based and Passive Sensing Features: Protocol for a Randomized Controlled Trial.

BACKGROUND: Psychotherapies, such as cognitive behavioral therapy (CBT), currently have the strongest evidence of durable symptom changes for most psychological disorders, such as anxiety disorders. Nevertheless, only about half of individuals treated with CBT benefit from it. Predictive algorithms, including digital assessments and passive sensing features, could better identify patients who would benefit from CBT, and thus, improve treatment choices. OBJECTIVE: This study aims to establish predictive features that forecast responses to transdiagnostic CBT in anxiety disorders and to investigate key mechanisms underlying treatment responses. METHODS: This study is a 2-armed randomized controlled clinical trial. We include patients with anxiety disorders who are randomized to either a transdiagnostic CBT group or a waitlist (referred to as WAIT). We index key features to predict responses prior to starting treatment using subjective self-report questionnaires, experimental tasks, biological samples, ecological momentary assessments, activity tracking, and smartphone-based passive sensing to derive a multimodal feature set for predictive modeling. Additional assessments take place weekly at mid- and posttreatment and at 6- and 12-month follow-ups to index anxiety and depression symptom severity. We aim to include 150 patients, randomized to CBT versus WAIT at a 3:1 ratio. The data set will be subject to full feature and important features selected by minimal redundancy and maximal relevance feature selection and then fed into machine leaning models, including eXtreme gradient boosting, pattern recognition network, and k-nearest neighbors to forecast treatment response. The performance of the developed models will be evaluated. In addition to predictive modeling, we will test specific mechanistic hypotheses (eg, association between self-efficacy, daily symptoms obtained using ecological momentary assessments, and treatment response) to elucidate mechanisms underlying treatment response. RESULTS: The trial is now completed. It was approved by the Cantonal Ethics Committee, Zurich. The results will be disseminated through publications in scientific peer-reviewed journals and conference presentations. CONCLUSIONS: The aim of this trial is to improve current CBT treatment by precise forecasting of treatment response and by understanding and potentially augmenting underpinning mechanisms and personalizing treatment. TRIAL REGISTRATION: ClinicalTrials.gov NCT03945617; https://clinicaltrials.gov/ct2/show/results/NCT03945617. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/42547.

Burst versus continuous delivery design in digital mental health interventions: Evidence from a randomized clinical trial.

Objective: Digital mental health interventions delivered via smartphone-based apps effectively treat various conditions; however, optimizing their efficacy while minimizing participant burden remains a key challenge. In this study, we investigated the potential benefits of a burst delivery design (i.e. interventions delivered only in pre-defined time intervals) in comparison to the continuous delivery of interventions. Methods: We randomly assigned 93 participants to the continuous delivery (CD) or burst delivery (BD) group. The CD group engaged in ReApp, a mobile app that increases positive cognitive reappraisal with a consistent delivery schedule that provides five prompts per day throughout the 3-week-long study, while the BD group received five daily prompts only in the first and third weeks of the study. Results: No significant differences were found between the groups in terms of adherence, mental health outcomes (specifically depressive and anxiety symptoms), level of perceived stress, and perceived helpfulness of intervention. The BD group showed a significantly decreased perceived difficulty of intervention over time. Conclusions: The results suggest that the burst delivery may be as suitable for digital mental health interventions as the continuous delivery. The perceived difficulty of the intervention declined more steeply for the BD group, indicating that it improved the feasibility of the positive cognitive reappraisal intervention without hurting its efficacy. This outcome may inform the design of less burdensome interventions with improved outcomes in future research.

The impact of doxycycline on human contextual fear memory.

RATIONALE:  Previous work identified an attenuating effect of the matrix metalloproteinase (MMP) inhibitor doxycycline on fear memory consolidation. This may present a new mechanistic approach for the prevention of trauma-related disorders. However, so far, this has only been unambiguously demonstrated in a cued delay fear conditioning paradigm, in which a simple geometric cue predicted a temporally overlapping aversive outcome. This form of learning is mainly amygdala dependent. Psychological trauma often involves the encoding of contextual cues, which putatively necessitates partly different neural circuits including the hippocampus. The role of MMP signalling in the underlying neural pathways in humans is unknown. METHODS: Here, we investigated the effect of doxycycline on configural fear conditioning in a double-blind placebo-controlled randomised trial with 100 (50 females) healthy human participants. RESULTS: Our results show that participants successfully learned and retained, after 1 week, the context-shock association in both groups. We find no group difference in fear memory retention in either of our pre-registered outcome measures, startle eye-blink responses and pupil dilation. Contrary to expectations, we identified elevated fear-potentiated startle in the doxycycline group early in the recall test, compared to the placebo group. CONCLUSION: Our results suggest that doxycycline does not substantially attenuate contextual fear memory. This might limit its potential for clinical application.

Attenuating human fear memory retention with minocycline: a randomized placebo-controlled trial.

Pavlovian fear conditioning is widely used as a pre-clinical model to investigate methods for prevention and treatment of anxiety and stress-related disorders. In this model, fear memory consolidation is thought to require synaptic remodeling, which is induced by signaling cascades involving matrix metalloproteinase 9 (MMP-9). Here we investigated the effect of the tetracycline antibiotic minocycline, an inhibitor of MMP-9, on fear memory retention. We conducted a pre-registered, randomized, double-blind, placebo-controlled trial in N = 105 healthy humans (N = 70 female), using a configural fear conditioning paradigm. We administered a single dose of minocycline before configural fear memory acquisition and assessed fear memory retention seven days later in a recall test. To index memory retention, we pre-registered fear-potentially startle (FPS) as our primary outcome, and pupil dilation as the secondary outcome. As control indices of memory acquisition, we analyzed skin conductance responses (SCR) and pupil dilation. We observed attenuated retention of configural fear memory in individuals treated with minocycline compared to placebo, as measured by our primary outcome. In contrast, minocycline did not affect fear memory acquisition or declarative contingency memory. Our findings provide in-vivo evidence for the inhibition of fear memory consolidation by minocycline. This could motivate further research into primary prevention, and given the short uptake time of minocycline, potentially also secondary prevention of PTSD after trauma.

A systematic review and meta-analysis of transdiagnostic cognitive behavioural therapies for emotional disorders.

Transdiagnostic cognitive behavioural psychotherapy (TD-CBT) may facilitate the treatment of emotional disorders. Here we investigate short- and long-term efficacy of TD-CBT for emotional disorders in individual, group and internet-based settings in randomized controlled trials (PROSPERO CRD42019141512). Two independent reviewers screened results from PubMed, MEDLINE, PsycINFO, Google Scholar, medRxiv and OSF Preprints published between January 2000 and June 2023, selected studies for inclusion, extracted data and evaluated risk of bias (Cochrane risk-of-bias tool 2.0). Absolute efficacy from pre- to posttreatment and relative efficacy between TD-CBT and control treatments were investigated with random-effects models. Of 56 identified studies, 53 (6,705 participants) were included in the meta-analysis. TD-CBT had larger effects on depression (g = 0.74, 95% CI = 0.57-0.92, P < 0.001) and anxiety (g = 0.77, 95% CI = 0.56-0.97, P < 0.001) than did controls. Across treatment formats, TD-CBT was superior to waitlist and treatment-as-usual. TD-CBT showed comparable effects to disorder-specific CBT and was superior to other active treatments for depression but not for anxiety. Different treatment formats showed comparable effects. TD-CBT was superior to controls at 3, 6 and 12 months but not at 24 months follow-up. Studies were heterogeneous in design and methodological quality. This review and meta-analysis strengthens the evidence for TD-CBT as an efficacious treatment for emotional disorders in different settings.

Feasibility, Adherence, and Effectiveness of Blended Psychotherapy for Severe Mental Illnesses: Scoping Review.

BACKGROUND: Blended psychotherapy (bPT) combines face-to-face psychotherapy with digital interventions to enhance the effectiveness of mental health treatment. The feasibility and effectiveness of bPT have been demonstrated for various mental health issues, although primarily for patients with higher levels of functioning. OBJECTIVE: This scoping review aims to investigate the feasibility, adherence, and effectiveness of bPT for the treatment of patients with severe mental illnesses (SMIs). METHODS: Following the PRISMA-ScR (Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews) guidelines, we conducted searches in PubMed, MEDLINE, Embase, PsycINFO, and PsycArticles for studies published until March 23, 2023. RESULTS: Out of 587 screened papers, we incorporated 25 studies encompassing 23 bPT interventions, involving a total of 2554 patients with SMI. The intervention formats and research designs exhibited significant variation. Our findings offer preliminary evidence supporting the feasibility of bPT for SMI, although there is limited research on adherence. Nevertheless, the summarized studies indicated promising attrition rates, spanning from 0% to 37%, implying a potential beneficial impact of bPT on adherence to SMI treatment. The quantity of evidence on the effects of bPT for SMI was limited and challenging to generalize. Among the 15 controlled trials, 4 concluded that bPT interventions were effective compared with controls. However, it is noteworthy that 2 of these studies used the same study population, and the control groups exhibited significant variations. CONCLUSIONS: Overall, our review suggests that while bPT appears promising as a treatment method, further research is necessary to establish its effectiveness for SMI. We discuss considerations for clinical implementation, directions, and future research.

Imager-A mobile health mental imagery-based ecological momentary intervention targeting reward sensitivity: A randomized controlled trial.

Robust reward sensitivity may help preserve mental well-being in the face of adversity and has been proposed as a key stress resilience factor. Here, we present a mobile health application, "Imager," which targets reward sensitivity by training individuals to create mental images of future rewarding experiences. We conducted a two-arm randomized controlled trial with 95 participants screened for reward sensitivity. Participants in the intervention group received an ecological momentary intervention-Imager, which encouraged participants to create mental images of rewarding events for 1 week. The control group participants received only ecological momentary assessment, without the instruction to generate mental images. Adherence to Imager was high; participants in the intervention group engaged in 88% of the planned activities. In the follow-up assessment, the intervention group reported less mental health symptoms, mainly in depression (ß = -0.34, df = 93, p = .004) and less perceived stress (ß = -0.18, df = 93, p = .035), than control group participants and compared with the baseline assessment. Our results show the positive effects of Imager on mental health symptoms. The encouraging effects of the app on mental health outcomes may lead to greater use of ecological momentary interventions in the clinical preventive practice of affective disorders.

German Version of the Mobile Agnew Relationship Measure: Translation and Validation Study.

BACKGROUND: The mobile Agnew Relationship Measure (mARM) is a self-report questionnaire for the evaluation of digital mental health interventions and their interactions with users. With the global increase in digital mental health intervention research, translated measures are required to conduct research with local populations. OBJECTIVE: The aim of this study was to translate and validate the original English version of the mARM into a German version (mARM-G). METHODS: A total of 2 native German speakers who spoke English as their second language conducted forward translation of the original items. This version was then back translated by 2 native German speakers with a fluent knowledge of English. An independent bilingual reviewer then compared these drafts and created a final German version. The mARM-G was validated by 15 experts in the field of mobile app development and 15 nonexperts for content validity and face validity; 144 participants were recruited to conduct reliability testing as well as confirmatory factor analysis. RESULTS: The content validity index of the mARM-G was 0.90 (expert ratings) and 0.79 (nonexperts). The face validity index was 0.89 (experts) and 0.86 (nonexperts). Internal consistency for the entire scale was Cronbach α=.91. Confirmatory factor analysis results were as follows: the chi-square statistic to df ratio was 1.66. Comparative Fit Index was 0.87 and the Tucker-Lewis Index was 0.86. The root mean square error of approximation was 0.07. CONCLUSIONS: The mARM-G is a valid and reliable tool that can be used for future studies in German-speaking countries.

Psychological Resilience Factors and Their Association With Weekly Stressor Reactivity During the COVID-19 Outbreak in Europe: Prospective Longitudinal Study.

BACKGROUND: Cross-sectional relationships between psychosocial resilience factors (RFs) and resilience, operationalized as the outcome of low mental health reactivity to stressor exposure (low "stressor reactivity" [SR]), were reported during the first wave of the COVID-19 pandemic in 2020. OBJECTIVE: Extending these findings, we here examined prospective relationships and weekly dynamics between the same RFs and SR in a longitudinal sample during the aftermath of the first wave in several European countries. METHODS: Over 5 weeks of app-based assessments, participants reported weekly stressor exposure, mental health problems, RFs, and demographic data in 1 of 6 different languages. As (partly) preregistered, hypotheses were tested cross-sectionally at baseline (N=558), and longitudinally (n=200), using mixed effects models and mediation analyses. RESULTS: RFs at baseline, including positive appraisal style (PAS), optimism (OPT), general self-efficacy (GSE), perceived good stress recovery (REC), and perceived social support (PSS), were negatively associated with SR scores, not only cross-sectionally (baseline SR scores; all P<.001) but also prospectively (average SR scores across subsequent weeks; positive appraisal (PA), P=.008; OPT, P<.001; GSE, P=.01; REC, P<.001; and PSS, P=.002). In both associations, PAS mediated the effects of PSS on SR (cross-sectionally: 95% CI -0.064 to -0.013; prospectively: 95% CI -0.074 to -0.0008). In the analyses of weekly RF-SR dynamics, the RFs PA of stressors generally and specifically related to the COVID-19 pandemic, and GSE were negatively associated with SR in a contemporaneous fashion (PA, P<.001; PAC,P=.03; and GSE, P<.001), but not in a lagged fashion (PA, P=.36; PAC, P=.52; and GSE, P=.06). CONCLUSIONS: We identified psychological RFs that prospectively predict resilience and cofluctuate with weekly SR within individuals. These prospective results endorse that the previously reported RF-SR associations do not exclusively reflect mood congruency or other temporal bias effects. We further confirm the important role of PA in resilience.

EEG wakefulness regulation in transdiagnostic patients after a recent suicide attempt.

OBJECTIVE: Decades of research have not yet produced statistically reliable predictors of preparatory behavior eventually leading to suicide attempts or deaths by suicide. As the nature of suicidal behavior is complex, it is best investigated in a transdiagnostic approach, while assessing objective markers, as proposed by the Research Domain Criteria (Cuthbert, 2013). METHODS: A 15-min resting-state EEG was recorded in 45 healthy controls, and 49 transdiagnostic in-patients with a recent (<6 months) suicide attempt. Brain arousal regulation in eyes-closed condition was assessed with the Vigilance Algorithm Leipzig (VIGALL) (Sander et al., 2015). RESULTS: A significant incline of median vigilance and vigilance slope was observed in patients within the first 3-min of the EEG recording. Additionally, a significant positive correlation of self-reported suicidal ideation with the vigilance slope over 15-min recording time, as well as a significant negative correlation with EEG vigilance stage A1 during the first 3-min was found. CONCLUSIONS: Transdiagnostic patients with a recent suicide attempt show a distinct vigilance regulation pattern. Further studies including a control group consisting of patients without life-time suicide attempts are needed to increase the clinical utility of the findings. SIGNIFICANCE: These findings might serve as potential objective markers of suicidal behavior.

EEG source functional connectivity in patients after a recent suicide attempt.

OBJECTIVE: Electroencephalogram (EEG) based frequency measures within the alpha frequency range (AFR), including functional connectivity, show potential in assessing the underlying pathophysiology of depression and suicide-related outcomes. We investigated the association between AFR connectivity, suicidal thoughts and behaviors, and depression in a transdiagnostic sample of patients after a recent suicide attempt (SA). METHODS: Lagged source-based measures of linear and nonlinear whole-brain connectivity within the standard AFR ([sAFR], 8-12 Hz) and the individually referenced AFR (iAFR) were applied to 70 15-minute resting-state EEGs from patients after a SA and 70 age- and gender-matched healthy controls (HC). Hypotheses were tested using network-based statistics and multiple regression models. RESULTS: Results showed no significant differences between patients after a SA and HC in any of the assessed connectivity modalities. However, a subgroup analysis revealed significantly increased nonlinear connectivity within the sAFR for patients after a SA with a depressive disorder or episode ([DD], n = 53) compared to matched HC. Furthermore, a multiple regression model, including significant main effects for group and global nonlinear connectivity within the sAFR outperformed all other models in explaining variance in depressive symptom severity. CONCLUSIONS: Our study further supports the importance of the AFR in pathomechanisms of suicidality and depression. The iAFR does not seem to improve validity of phase-based connectivity. SIGNIFICANCE: Our results implicate distinct neurophysiological patterns in suicidal subgroups. Exploring the potential of these patterns for treatment stratification might advance targeted interventions for suicidal thoughts and behaviors.

Investigating Relationships Among Self-Efficacy, Mood, and Anxiety Using Digital Technologies: Randomized Controlled Trial.

BACKGROUND: Digital tools assessing momentary parameters and offering interventions in people's daily lives play an increasingly important role in mental health research and treatment. Ecological momentary assessment (EMA) makes it possible to assess transient mental health states and their parameters. Ecological momentary interventions (EMIs) offer mental health interventions that fit well into individuals' daily lives and routines. Self-efficacy is a transdiagnostic construct that is commonly associated with positive mental health outcomes. OBJECTIVE: The aim of our study assessing mood, specific self-efficacy, and other parameters using EMA was 2-fold. First, we wanted to determine the effects of daily assessed moods and dissatisfaction with social contacts as well as the effects of baseline variables, such as depression, on specific self-efficacy in the training group (TG). Second, we aimed to explore which variables influenced both groups' positive and negative moods during the 7-day study period. METHODS: In this randomized controlled trial, we applied digital self-efficacy training (EMI) to 93 university students with elevated self-reported stress levels and daily collected different parameters, such as mood, dissatisfaction with social contacts, and specific self-efficacy, using EMA. Participants were randomized to either the TG, where they completed the self-efficacy training combined with EMA, or the control group, where they completed EMA only. RESULTS: In total, 93 university students participated in the trial. Positive momentary mood was associated with higher specific self-efficacy in the evening of the same day (b=0.15, SE 0.05, P=.005). Higher self-efficacy at baseline was associated with reduced negative mood during study participation (b=-0.61, SE 0.30, P=.04), while we could not determine an effect on positive mood. Baseline depression severity was significantly associated with lower specific self-efficacy over the week of the training (b=-0.92, SE 0.35, P=.004). Associations between higher baseline anxiety with higher mean negative mood (state anxiety: b=0.78, SE 0.38, P=.04; trait anxiety: b=0.73, SE 0.33, P=.03) and lower mean positive mood (b=-0.64, SE 0.28, P=.02) during study participation were found. Emotional flexibility was significantly enhanced in the TG. Additionally, dissatisfaction with social contacts was associated with both a decreased positive mood (b=-0.56, SE 0.15, P<.001) and an increased negative mood (b=0.45, SE 0.12, P<.001). CONCLUSIONS: This study showed several significant associations between mood and self-efficacy as well as those between mood and anxiety in students with elevated stress levels, for example, suggesting that improving mood in people with low mood could enhance the effects of digital self-efficacy training. In addition, engaging in 1-week self-efficacy training was associated with increased emotional flexibility. Future work is needed to replicate and investigate the training's effects in other groups and settings. TRIAL REGISTRATION: ClinicalTrials.gov NCT05617248; https://clinicaltrials.gov/study/NCT05617248.

Dynamic Modelling of Mental Resilience in Young Adults: Protocol for a Longitudinal Observational Study (DynaM-OBS).

BACKGROUND: Stress-related mental disorders are highly prevalent and pose a substantial burden on individuals and society. Improving strategies for the prevention and treatment of mental disorders requires a better understanding of their risk and resilience factors. This multicenter study aims to contribute to this endeavor by investigating psychological resilience in healthy but susceptible young adults over 9 months. Resilience is conceptualized in this study as the maintenance of mental health or quick recovery from mental health perturbations upon exposure to stressors, assessed longitudinally via frequent monitoring of stressors and mental health. OBJECTIVE: This study aims to investigate the factors predicting mental resilience and adaptive processes and mechanisms contributing to mental resilience and to provide a methodological and evidence-based framework for later intervention studies. METHODS: In a multicenter setting, across 5 research sites, a sample with a total target size of 250 young male and female adults was assessed longitudinally over 9 months. Participants were included if they reported at least 3 past stressful life events and an elevated level of (internalizing) mental health problems but were not presently affected by any mental disorder other than mild depression. At baseline, sociodemographic, psychological, neuropsychological, structural, and functional brain imaging; salivary cortisol and α-amylase levels; and cardiovascular data were acquired. In a 6-month longitudinal phase 1, stressor exposure, mental health problems, and perceived positive appraisal were monitored biweekly in a web-based environment, while ecological momentary assessments and ecological physiological assessments took place once per month for 1 week, using mobile phones and wristbands. In a subsequent 3-month longitudinal phase 2, web-based monitoring was reduced to once a month, and psychological resilience and risk factors were assessed again at the end of the 9-month period. In addition, samples for genetic, epigenetic, and microbiome analyses were collected at baseline and at months 3 and 6. As an approximation of resilience, an individual stressor reactivity score will be calculated. Using regularized regression methods, network modeling, ordinary differential equations, landmarking methods, and neural net-based methods for imputation and dimension reduction, we will identify the predictors and mechanisms of stressor reactivity and thus be able to identify resilience factors and mechanisms that facilitate adaptation to stressors. RESULTS: Participant inclusion began in October 2020, and data acquisition was completed in June 2022. A total of 249 participants were assessed at baseline, 209 finished longitudinal phase 1, and 153 finished longitudinal phase 2. CONCLUSIONS: The Dynamic Modelling of Resilience-Observational Study provides a methodological framework and data set to identify predictors and mechanisms of mental resilience, which are intended to serve as an empirical foundation for future intervention studies. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/39817.

Pharmacological memory modulation to augment trauma-focused psychotherapy for PTSD: a systematic review of randomised controlled trials.

Trauma-focused psychotherapy (tf-PT) is the first-line treatment for posttraumatic stress disorder (PTSD). Tf-PT focuses on processing and modulating trauma memories. Not all patients benefit, however, and there is room for improvement of efficacy. Pharmacologically augmenting trauma memory modulation in the context of tf-PT may help optimise treatment outcome. To systematically review effects of pharmacologically augmented memory modulation in the context of tf-PT for PTSD (PROSPERO preregistration ID: CRD42021230623). We conducted a systematic review of randomised controlled trials of psychotherapy treatment for PTSD. We included placebo-controlled studies that augmented at least one treatment session pharmacologically targeting memory extinction or reconsolidation. We calculated post-treatment between group (pharmacological augmentation vs placebo control) effect sizes of PTSD symptom severity. We included 13 RCTs. There was large heterogeneity in augmentation procedure and methodological quality. Four studies showed significantly greater PTSD symptom reduction in the pharmacological augmentation group (propranolol, hydrocortisone, dexamethasone, D-cycloserine) compared to placebo. Seven studies showed no significant effect of pharmacological augmentation compared to placebo (D-cycloserine, rapamycin, mifepristone, propranolol, mifepristone combined with D-cycloserine, methylene blue). Two studies showed significantly smaller PTSD symptom reduction in the pharmacological augmentation group (D-cycloserine, dexamethasone) compared to placebo. Results of pharmacological augmentation were mixed overall and heterogenous for the pharmacological agents tested in more than one study. Additional studies and replications are needed to identify which pharmacological agents work, in which combination and to identify patient groups that benefit most to tailor PTSD treatment.

Positive Prospective Mental Imagery Characteristics in Young Adults and Their Associations with Depressive Symptoms.

Background: Positive prospective mental imagery plays an important role in mental well-being, and depressive symptoms have been associated with difficulties in generating positive prospective mental images (PPMIs). We used a mobile app to gather PPMIs generated by young adults during the COVID-19 pandemic and analyzed content, characteristics, and associations with depressive symptoms. Methods: This is a secondary analysis of a randomized controlled trial with 95 healthy young adults allocated into two groups (intervention and control). Participants used the mobile app decreasing mental health symptoms for seven consecutive days. Fifty participants in the intervention group reported PPMIs at least three times per day using a mobile app inducing PPMI generation. We categorized entries into themes and applied moderation models to investigate associations between PPMI characteristics and depressive symptoms. Results: We distinguished 25 PPMI themes. The most frequent were related to consuming food and drinks, watching TV/streaming platforms, and doing sports. Vividness and ease of generation of PPMIs, but not their anticipation, pleasure intensity or number of engagements with the app were associated with fewer depressive symptoms. Conclusions: We identified PPMI themes in young adults and found significant negative associations between depressive symptoms and vividness and generation ease of PPMIs. These results may inform prevention and intervention science, including the design of personalized interventions. We discuss implications for future studies and treatment development for individuals experiencing diminished PPMI. Supplementary Information: The online version contains supplementary material available at 10.1007/s10608-023-10378-5.

Autism spectrum disorders in adults and the autonomic nervous system: Heart rate variability markers in the diagnostic procedure.

The diagnostic assessment of autism spectrum disorders (ASD) in adults is a challenging and time-consuming procedure. In order to address the lack of specialised health-care professionals and improve the waiting time, we aimed to identify specific electrocardiogram (ECG) derived Heart Rate Variability (HRV) parameters that could be used for diagnostic purposes. 152 patients were diagnosed based on a standardised clinical procedure and assigned to one of three groups: ASD (n = 56), any other psychiatric disorder (OD) (n = 72), and patients with no diagnosis (ND) (n = 24). Groups were compared using ANOVA. Discriminative power of biological parameters and the clinical assessment were compared using receiver operating characteristic curves (ROCs). Patients with ASD showed reduced parasympathetic and increased sympathetic activity compared to ND. The accuracy determined by the area under the curve (AUC) of the biological parameters for discrimination between ASD vs. pooled OD/ND was 0.736 (95% CI = 0.652-0.820), compared to .856 (95% CI = 0.795-0.917) for the extensive clinical assessment. Our results confirmed the dysregulation of the autonomic nervous system in ASD with reduced parasympathetic and increased sympathetic activity as compared to ND. The discriminative power of biological markers including HRV was considerable and could supplement less sophisticated clinical assessments.

Development of a digital biomarker and intervention for subclinical depression: study protocol for a longitudinal waitlist control study.

BACKGROUND: Depression remains a global health problem, with its prevalence rising worldwide. Digital biomarkers are increasingly investigated to initiate and tailor scalable interventions targeting depression. Due to the steady influx of new cases, focusing on treatment alone will not suffice; academics and practitioners need to focus on the prevention of depression (i.e., addressing subclinical depression). AIM: With our study, we aim to (i) develop digital biomarkers for subclinical symptoms of depression, (ii) develop digital biomarkers for severity of subclinical depression, and (iii) investigate the efficacy of a digital intervention in reducing symptoms and severity of subclinical depression. METHOD: Participants will interact with the digital intervention BEDDA consisting of a scripted conversational agent, the slow-paced breathing training Breeze, and actionable advice for different symptoms. The intervention comprises 30 daily interactions to be completed in less than 45 days. We will collect self-reports regarding mood, agitation, anhedonia (proximal outcomes; first objective), self-reports regarding depression severity (primary distal outcome; second and third objective), anxiety severity (secondary distal outcome; second and third objective), stress (secondary distal outcome; second and third objective), voice, and breathing. A subsample of 25% of the participants will use smartwatches to record physiological data (e.g., heart-rate, heart-rate variability), which will be used in the analyses for all three objectives. DISCUSSION: Digital voice- and breathing-based biomarkers may improve diagnosis, prevention, and care by enabling an unobtrusive and either complementary or alternative assessment to self-reports. Furthermore, our results may advance our understanding of underlying psychophysiological changes in subclinical depression. Our study also provides further evidence regarding the efficacy of standalone digital health interventions to prevent depression. Trial registration Ethics approval was provided by the Ethics Commission of ETH Zurich (EK-2022-N-31) and the study was registered in the ISRCTN registry (Reference number: ISRCTN38841716, Submission date: 20/08/2022).

Effect of the Matrix Metalloproteinase Inhibitor Doxycycline on Human Trace Fear Memory.

Learning to predict threat is of adaptive importance, but aversive memory can also become disadvantageous and burdensome in clinical conditions such as posttraumatic stress disorder (PTSD). Pavlovian fear conditioning is a laboratory model of aversive memory and thought to rely on structural synaptic reconfiguration involving matrix metalloproteinase (MMP)9 signaling. It has recently been suggested that the MMP9-inhibiting antibiotic doxycycline, applied before acquisition training in humans, reduces fear memory retention after one week. This previous study used cued delay fear conditioning, in which predictors and outcomes overlap in time. However, temporal separation of predictors and outcomes is common in clinical conditions. Learning the association of temporally separated events requires a partly different neural circuitry, for which the role of MMP9 signaling is not yet known. Here, we investigate the impact of doxycycline on long-interval (15 s) trace fear conditioning in a randomized controlled trial with 101 (50 females) human participants. We find no impact of the drug in our preregistered analyses. Exploratory post hoc analyses of memory retention suggested a serum level-dependent effect of doxycycline on trace fear memory retention. However, effect size to distinguish CS+/CS- in the placebo group turned out to be smaller than in previously used delay fear conditioning protocols, which limits the power of statistical tests. Our results suggest that doxycycline effect on trace fear conditioning in healthy individuals is smaller and less robust than anticipated, potentially limiting its clinical application potential.

A recent suicide attempt and the heartbeat: Electrophysiological findings from a trans-diagnostic cohort of patients and healthy controls.

Suicidal behavior is influenced by a multitude of factors, making prediction and prevention of suicide attempts (SA) a challenge. A useful tool to uncover underlying pathophysiology or propose new therapy approaches are biomarkers, especially within the context of point-of-care tests. Heart rate variability (HRV) is a well-established biomarker of mental health, and measures the activity of the sympathetic and parasympathetic nervous system (PNS). Previous studies reported a correlation between lower PNS activity and suicidality. However, most studies involved participants from a healthy population, patients without history of suicide attempts, or patients with a single diagnosis. 52 in-patients with a recent suicide attempt (<6 months), and 43 controls without history of SA or psychiatric diagnoses confirmed study participation. The included patients age ranged between 18 and 65 years, 65% had psychiatric comorbidities. Patients with dementia, cognitive impairments, acute psychosis, chronic non suicidal self-harming behavior, or current electroconvulsive therapy were excluded. A 15-min resting state electrocardiography was recorded with two bipolar electrodes attached to the right and left insides of the wrists. The multiple regression analyses showed lower parasympathetic, and higher sympathetic activity in patients compared to controls. Partial correlation found a positive trend result between self-reported suicidality and the very low frequency band. ROC curve analysis revealed an acceptable to excellent clinical accuracy of HRV parameters. Therefore, HRV parameters could be reliable discriminative biomarkers between in-patients with a recent SA and healthy controls. One limitation is the lack of a control group consisting of in-patients without life-time suicidal ideation or attempts.