Ulrich Kirk

Background: Social anxiety disorder is a chronic and disabling condition with limited response to standard therapies. Low-dose psilocybin may enhance the effectiveness of exposure-based treatments by modulating neural circuits associated with fear and avoidance. Virtual reality exposure therapy offers a controlled and individualized platform for intervention.Objective: This phase 2b, double-blind clinical trial (n = 32) investigates feasibility and tolerability of low-dose psilocybin as an adjunct to virtual reality exposure therapy in individuals with social anxiety disorder.Design and Methods: Participants will be randomized to receive either low-dose psilocybin or placebo alongside virtual reality exposure therapy. The primary outcome is the change in social anxiety symptoms, measured by the Liebowitz Social Anxiety Scale (LSAS). The primary endpoint is a Cohen’s d ≥ 0.5 for LSAS reduction in the psilocybin group versus placebo. Secondary outcomes include identification of multimodal biomarkers predictive of treatment response. Neuroimaging (e.g., amygdala reactivity, thalamo-cortical connectivity), psychophysiological (e.g., heart rate variability, galvanic skin response, sleep quality), and behavioral task measures (e.g., Affective Shift Task, Emotional Go/No-Go Task) will be analyzed to stratify participants and predict therapeutic response. Successful biomarker stratification is defined as a significant correlation with LSAS change and classification accuracy >70%.Conclusion: This study will provide proof-of-concept evidence for low-dose psilocybin as an adjunct to virtual reality exposure therapy in social anxiety disorder and evaluate multimodal biomarkers for patient stratification. Positive results will support progression to a larger phase 3 trial and inform precision-based approaches for treatment of social anxiety disorder.

Fear-based disorders affect millions worldwide, yet current treatments show limited effectiveness for many patients. While mindfulness is increasingly used clinically for anxiety and trauma disorders, the neural mechanisms underlying its effects on fear processing remain unclear. We conducted a randomized controlled trial using 7T fMRI to test whether mindfulness training enhances fear extinction recall—a process critical for recovery from these disorders. Healthy participants received four weeks of app-based mindfulness meditation ( n = 27) or served as waitlist controls ( n = 28), then underwent fear conditioning and extinction recall testing. Mindfulness training specifically enhanced extinction recall, reducing threat responses to extinguished cues by both physiological (skin conductance, p =.028) and neural measures. Critically, our findings reveal a candidate mechanism: mindfulness reduced activation in subcortical threat-processing regions (amygdala, striatum, supplementary motor area) without enhancing cognitive control areas, a pattern consistent with direct modulation of fear circuits rather than top-down inhibition, though top-down contributions cannot be excluded. This pattern is consistent with mindfulness enhancing safety memory retrieval through implicit rather than explicit emotion regulation, providing preliminary neurobiological evidence relevant to optimizing mindfulness-based treatments. Our findings suggest that mindfulness training, whether administered before or alongside exposure therapy, could potentially enhance therapeutic outcomes by improving the consolidation and retrieval of safety memories, although replication in larger clinical samples is needed.

To test whether a 10-day mindfulness program delivered through the ŌURA app improves sleep and stress in healthy adults, eighty-one adults were randomized to mindfulness (n = 49) or waitlist control (n = 32). Participants wore an Ōura ring during baseline, intervention/wait-list, and 4-week follow-up, recording sleep efficiency, total, deep, and light sleep, plus sleep-onset time. Questionnaires—Pittsburgh sleep quality index (PSQI), perceived stress scale (PSS), Copenhagen burnout inventory (CBI), and mindful attention awareness scale (MAAS)—were completed pre- and post-intervention and at follow-up. Mixed-model ANOVAs revealed significant group × time interactions for sleep efficiency, total sleep, deep and light sleep, and sleep-onset time (all p s < 0.031). Results showed that the mindfulness group improved after 10 days (all p s < 0.021); gains persisted at follow-up except for deep sleep. The mindfulness group exhibited increased personal burnout ( p = 0.021) immediately post-intervention, though this returned toward baseline at follow-up. In addition, the mindfulness showed higher MAAS scores ( p = 0.017). During mindfulness sessions heart rate fell ( p = 0.011) and heart-rate variability rose ( p = 0.029). A brief, app-based mindfulness program produced sustained improvements in sleep efficiency and enhanced HRV, demonstrating that digital mindfulness can favorably influence biobehavioral sleep-stress metrics. Trial Registration : ClinicalTrials.gov: NCT07469644

Background: Anxiety and depressive disorders affect hundreds of millions globally, with substantial barriers limiting access to evidence-based treatments like cognitive behavioral therapy. Digital mental health interventions offer potential solutions to improve access to support. However, evidence of efficacy through randomized controlled trials is essential for clinical adoption. Objective: This study evaluated the efficacy of the Headspace Anxiety and Depression Program, a digitally delivered 21-session intervention grounded in the Unified Protocol that integrates cognitive behavioral and mindfulness-based strategies to target common drivers of emotional disorders, compared to a waitlist control group. Primary aims were to assess reductions in anxiety (Generalized Anxiety Disorder-7 [GAD-7]) and depression (Patient Health Questionnaire-8 [PHQ-8]) symptoms. Secondary aims examined improvements in sleep quality (Pittsburgh Sleep Quality Index), perceived stress (Perceived Stress Scale-10), mindfulness (Mindful Attention Awareness Scale), and overall well-being (Warwick-Edinburgh Mental Well-Being Scale), as well as clinical remission and treatment response rates. Methods: A fully remote, 2-arm parallel-group randomized controlled trial was conducted with 168 participants (aged ≥18 years) who had clinically significant anxiety (GAD-7≥10) or depression symptoms (PHQ-8≥10). Participants were randomized to either the Headspace Anxiety and Depression Program (n=84) or waitlist control (n=84). The intervention consisted of 21 daily sessions (5-10 minutes each) delivered via the Headspace app. Primary (GAD-7 and PHQ-8) and secondary outcomes (Pittsburgh Sleep Quality Index, Perceived Stress Scale-10, Mindful Attention Awareness Scale, and Warwick-Edinburgh Mental Well-Being Scale) were assessed at baseline, postintervention, and a 3-week follow-up using intention-to-treat analysis with mixed-model ANOVAs. Results: Study retention was high, with the majority (154/168, 91.7%) of participants completing the 3-week follow-up visit, and no serious adverse events were reported. Intervention adherence was high, with 82.1% (69/84) in the intervention group completing all 21 sessions. Significant group×time interactions were observed for both primary outcomes (P<.001). The Headspace group showed substantial reductions in anxiety symptoms (GAD-7: 34.5% reduction from baseline: mean 11.9, SD 2.8 to follow-up: mean 7.8, SD 2.3; η2p=0.350) and depression symptoms (PHQ-8: 33.9% reduction from baseline: mean 12.1, SD 2.8 to follow-up: mean 8.0, SD 2.0; η2p=0.370), while the control group did not show significant reductions. Combined anxiety and depression remission rates were significantly higher in the Headspace group (18/84, 21.4%) versus controls (7/84, 8.3%; P=.03), as were treatment response rates (23/84, 27.3% vs 2/84, 2.3%; P=.03). Participants in the Headspace group also demonstrated significant improvements in secondary outcomes, including sleep quality (30.2% improvement), perceived stress (13.2% reduction), mindfulness (10.3% increase), and mental well-being (10.7% increase). Conclusions: The Headspace Anxiety and Depression Program demonstrated significant efficacy in reducing anxiety and depression symptoms comparable to established treatments. Benefits were sustained at the 3-week follow-up. These findings support the potential of evidence-based transdiagnostic digital mental health interventions to address critical gaps in mental health care delivery. Trial Registration: ClinicalTrials.gov NCT06434883; https://clinicaltrials.gov/study/NCT06434883

BACKGROUND Anxiety and depressive disorders affect hundreds of millions globally, with substantial barriers limiting access to evidence-based treatments like cognitive behavioral therapy. Digital mental health interventions offer potential solutions to improve access to support. However, evidence of efficacy through randomized controlled trials is essential for clinical adoption. OBJECTIVE This study evaluated the efficacy of the Headspace Anxiety and Depression Program, a digitally delivered 21-session intervention grounded in the Unified Protocol that integrates cognitive behavioral and mindfulness-based strategies to target common drivers of emotional disorders, compared to a waitlist control group. Primary aims were to assess reductions in anxiety (Generalized Anxiety Disorder-7 [GAD-7]) and depression (Patient Health Questionnaire-8 [PHQ-8]) symptoms. Secondary aims examined improvements in sleep quality (Pittsburgh Sleep Quality Index), perceived stress (Perceived Stress Scale-10), mindfulness (Mindful Attention Awareness Scale), and overall well-being (Warwick-Edinburgh Mental Well-Being Scale), as well as clinical remission and treatment response rates. METHODS A fully remote, 2-arm parallel-group randomized controlled trial was conducted with 168 participants (aged ≥18 years) who had clinically significant anxiety (GAD-7≥10) or depression symptoms (PHQ-8≥10). Participants were randomized to either the Headspace Anxiety and Depression Program (n=84) or waitlist control (n=84). The intervention consisted of 21 daily sessions (5-10 minutes each) delivered via the Headspace app. Primary (GAD-7 and PHQ-8) and secondary outcomes (Pittsburgh Sleep Quality Index, Perceived Stress Scale-10, Mindful Attention Awareness Scale, and Warwick-Edinburgh Mental Well-Being Scale) were assessed at baseline, postintervention, and a 3-week follow-up using intention-to-treat analysis with mixed-model ANOVAs. RESULTS Study retention was high, with the majority (154/168, 91.7%) of participants completing the 3-week follow-up visit, and no serious adverse events were reported. Intervention adherence was high, with 82.1% (69/84) in the intervention group completing all 21 sessions. Significant group×time interactions were observed for both primary outcomes (P<.001). The Headspace group showed substantial reductions in anxiety symptoms (GAD-7: 34.5% reduction from baseline: mean 11.9, SD 2.8 to follow-up: mean 7.8, SD 2.3; η2p=0.350) and depression symptoms (PHQ-8: 33.9% reduction from baseline: mean 12.1, SD 2.8 to follow-up: mean 8.0, SD 2.0; η2p=0.370), while the control group did not show significant reductions. Combined anxiety and depression remission rates were significantly higher in the Headspace group (18/84, 21.4%) versus controls (7/84, 8.3%; P=.03), as were treatment response rates (23/84, 27.3% vs 2/84, 2.3%; P=.03). Participants in the Headspace group also demonstrated significant improvements in secondary outcomes, including sleep quality (30.2% improvement), perceived stress (13.2% reduction), mindfulness (10.3% increase), and mental well-being (10.7% increase). CONCLUSIONS The Headspace Anxiety and Depression Program demonstrated significant efficacy in reducing anxiety and depression symptoms comparable to established treatments. Benefits were sustained at the 3-week follow-up. These findings support the potential of evidence-based transdiagnostic digital mental health interventions to address critical gaps in mental health care delivery. CLINICALTRIAL ClinicalTrials.gov NCT06434883; https://clinicaltrials.gov/study/NCT06434883

Background: Insomnia is the most commonly reported sleep disturbance and significantly impacts mental health and quality of life. Traditional treatments for insomnia include pharmacological interventions or cognitive behavioral therapy for insomnia (CBT-I), but these options may not be accessible to everyone who needs treatment. Objective: This study aims to assess the effectiveness of the app-based Headspace Sleep Program in adults with clinical insomnia on sleep disturbance and mental health outcomes, compared with a waitlist control group. Methods: This randomized controlled trial included 132 adults with clinical insomnia who were assigned to either the Headspace Sleep Program (an 18-session self-guided, in-app program utilizing CBT-I techniques augmented by mindfulness) or a waitlist control group. Sleep disturbance outcomes were assessed by changes in insomnia symptoms (measured using the Insomnia Severity Index) and sleep efficiency (measured via sleep diary and actigraphy). Mental health outcomes included perceived stress (measured by the 10-item Perceived Stress Scale), depressive symptoms (measured by the 8-item Patient Health Questionnaire), sleep quality (measured by the Pittsburgh Sleep Quality Index), anxiety symptoms (measured by the 7-item Generalized Anxiety Disorder Scale), and mindfulness (measured by the Mindful Attention Awareness Scale). Changes from baseline to postintervention and follow-up were assessed for each outcome. Results: Participants had a mean (SD) age of 37.2 (10.6) years, with 69 out of 132 (52.3%) identifying as female. Those randomized to the Headspace Sleep Program group experienced significantly greater improvements in insomnia symptoms from baseline to postintervention and follow-up compared with participants in the waitlist control group (P<.001, η²p=0.107). Improvements from baseline to postintervention and follow-up were also observed in the Headspace Sleep Program group for sleep efficiency, as measured by both sleep diary (P=.01, η²p=.03) and actigraphy outcomes (P=.01, η²p=.03). Participants in the Headspace Sleep Program group showed greater improvements in insomnia remission rates (8/66, 12%, at postintervention and 9/66, 14%, at follow-up) and treatment response (11/66, 17%, at postintervention and 15/66, 23%, at follow-up) compared with the control group (remission rate 2/66, 3%, at postintervention and 0/66, 0%, at follow-up; treatment response 3/66, 5%, at postintervention and 1/66, 2%, at follow-up). The results suggest significant improvements in depressive symptoms (P=.01, η²p=.04), anxiety symptoms (P=.02, η²p=.02), and mindfulness (P=.01, η²p=.03) in the Headspace Sleep Program group. Conclusions: The Headspace Sleep Program is an effective intervention for improving sleep disturbances in adults with clinical insomnia. Trial Registration: ClinicalTrials.gov NCT05872672; https://clinicaltrials.gov/ct2/show/NCT05872672

Journal of Medical Internet Research - International Scientific Journal for Medical Research, Information and Communication on the Internet #Preprint #PeerReviewMe: Warning: This is a unreviewed preprint. Readers are warned that the document has not been peer-reviewed by expert/patient reviewers or an academic editor, may contain misleading claims, and is likely to undergo changes before final publication, if accepted, or may have been rejected/withdrawn. Readers with interest and expertise are encouraged to sign up as peer-reviewer, if the paper is within an open peer-review period. Please cite this preprint only for review purposes or for grant applications and CVs (if you are the author). Background: Insomnia is the most commonly reported sleep disturbance and significantly impacts mental health and quality of life. Traditional treatments for insomnia include pharmacological interventions or cognitive behavioral therapy for insomnia (CBT-I), but these options may not be accessible to everyone who needs treatment. Objective: This study aims to assess the effectiveness of the app-based Headspace Sleep Program in adults with clinical insomnia on sleep disturbance and mental health outcomes, compared with a waitlist control group. Methods: This randomized controlled trial included 132 adults with clinical insomnia who were assigned to either the Headspace Sleep Program (an 18-session self-guided, in-app program utilizing CBT-I techniques augmented by mindfulness) or a waitlist control group. Sleep disturbance outcomes were assessed by changes in insomnia symptoms (measured using the Insomnia Severity Index) and sleep efficiency (measured via sleep diary and actigraphy). Mental health outcomes included perceived stress (measured by the 10-item Perceived Stress Scale), depressive symptoms (measured by the 8-item Patient Health Questionnaire), sleep quality (measured by the Pittsburgh Sleep Quality Index), anxiety symptoms (measured by the 7-item Generalized Anxiety Disorder Scale), and mindfulness (measured by the Mindful Attention Awareness Scale). Changes from baseline to postintervention and follow-up were assessed for each outcome. Results: Participants had a mean (SD) age of 37.2 (10.6) years, with 69 out of 132 (52.3%) identifying as female. Those randomized to the Headspace Sleep Program group experienced significantly greater improvements in insomnia symptoms from baseline to postintervention and follow-up compared with participants in the waitlist control group (P<.001, η²p=0.107). Improvements from baseline to postintervention and follow-up were also observed in the Headspace Sleep Program group for sleep efficiency, as measured by both sleep diary (P=.01, η²p=.03) and actigraphy outcomes (P=.01, η²p=.03). Participants in the Headspace Sleep Program group showed greater improvements in insomnia remission rates (8/66, 12%, at postintervention and 9/66, 14%, at follow-up) and treatment response (11/66, 17%, at postintervention and 15/66, 23%, at follow-up) compared with the control group (remission rate 2/66, 3%, at postintervention and 0/66, 0%, at follow-up; treatment response 3/66, 5%, at postintervention and 1/66, 2%, at follow-up). The results suggest significant improvements in depressive symptoms (P=.01, η²p=.04), anxiety symptoms (P=.02, η²p=.02), and mindfulness (P=.01, η²p=.03) in the Headspace Sleep Program group. Conclusions: The Headspace Sleep Program is an effective intervention for improving sleep disturbances in adults with clinical insomnia. Trial Registration: ClinicalTrials.gov NCT05872672; https://clinicaltrials.gov/ct2/show/NCT05872672

Background: Stress-related mental health disorders have steadily increased and contributed to a worldwide disease burden with up to 50% experiencing a stress-related mental health disorder worldwide. Data suggest that only approximately 20%-65% of individuals receive treatment. This gap in receiving treatment may be attributed to barriers such as limited treatment access, negative stigma surrounding mental health treatment, approachability (ie, not having a usual treatment plan or provider), affordability (ie, lack of insurance coverage and high treatment cost), and availability (ie, long waits for appointments) leaving those who need treatment without necessary care. To mitigate the limited access mental health treatment, there has been a rise in the application and study of digital mental health interventions. As such, there is an urgent need and opportunity for effective digital mental health interventions to alleviate stress symptoms, potentially reducing adverse outcomes of stress-related disorders.Objective: This study examined if app-based guided mindfulness could improve subjective levels of stress and influence physiological markers of stress reactivity in a population with elevated symptoms of stress.Methods: The study included 163 participants who had moderate to high perceived stress as assessed by the Perceived Stress Scale (PSS-10). Participants were randomly allocated to 1 of 5 groups: a digital guided program designed to alleviate stress (Managing Stress), a digital mindfulness fundamentals course (Basics), digitally delivered breathing exercises, an active control intervention (Audiobook), and a Waitlist Control group. The 3 formats of mindfulness interventions (Managing Stress, Basics, and Breathing) all had a total duration of 300 minutes spanning 20-30 days. Primary outcome measures were perceived stress using the PSS-10, self-reported sleep quality using the Pittsburgh Sleep Quality Index, and trait mindfulness using the Mindful Attention Awareness Scale. To probe the effects of physiological stress, an acute stress manipulation task was included, specifically the cold pressor task (CPT). Heart rate variability was collected before, during, and after exposure to the CPT and used as a measure of physiological stress.Results: The results showed that PSS-10 and Pittsburgh Sleep Quality Index scores for the Managing Stress (all P<.001) and Basics (all P≤.002) groups were significantly reduced between preintervention and postintervention periods, while no significant differences were reported for the other groups. No significant differences among groups were reported for Mindful Attention Awareness Scale (P=.13). The physiological results revealed that the Managing Stress (P<.001) and Basics (P=.01) groups displayed reduced physiological stress reactivity between the preintervention and postintervention periods on the CPT. There were no significant differences reported for the other groups.Conclusions: These results demonstrate efficacy of app-based mindfulness in a population with moderate to high stress on improving self-reported stress, sleep quality, and physiological measures of stress during an acute stress manipulation task.Trial Registration: ClinicalTrials.gov NCT05832632; https://www.clinicaltrials.gov/ct2/show/NCT05832632