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.

Positive autobiographical memories to counteract low mood in remitted depression: A longitudinal daily-life investigation.

Positive autobiographical memories (AMs) have the potential to repair low mood, but previously depressed individuals have difficulty leveraging their positive AMs for emotion regulation purposes. We examined whether previously depressed individuals benefit from guided, deliberate recollection of preselected AMs to counteract low mood in daily life, utilizing individuals' smartphones to facilitate recollection. Sixty participants enrolled in 2020 were randomly allocated to retrieval of positive or everyday activity AMs and completed ecological momentary assessment of emotional experience for 3 weeks. Participants first created a pool of six memories for the digital AM diary. This was followed by a training week with two recollection tasks daily and a 2-week follow-up period where the diary could be used spontaneously. The positive condition experienced a greater increase in feelings of happiness and a greater decrease in feelings of sadness from pre- to post-AM recollection. While participants in the positive condition used the AM technique more frequently overall during the 2-week follow-up, the effect of condition was moderated by changes in feelings of sadness. The more participants experienced an emotional benefit during the training week, the more they used it spontaneously. Emotional vividness of untrained positive AMs at the 2-week follow-up differed depending on whether they were assessed before or after the first pandemic lockdown. Residual depressive symptoms decreased in both conditions over the study course, while mental well-being remained unchanged. Strengthening positive, self-affirming AMs in daily life may provide a tool to support regulation of transient low mood in those remitted from depression. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Examining bi-directional links between loneliness, social connectedness and sleep from a trait and state perspective.

Greater loneliness as well as a lack of social connectedness have often been associated with poorer sleep. However, the temporal dynamics and direction of these associations remain unclear. Aim of the current study was to examine bi-directional associations between loneliness/social connectedness and sleep in 48 stress-exposed medical students during their first medical internship, considered a period of heightened stress. We obtained trait-level questionnaire data on loneliness and global sleep completed before and during the internship as well as state-level diary- and wearable-based data on daily changes in social connectedness and sleep collected twice over the period of seven consecutive days, once before and once during the internship. Bi-directional associations among greater loneliness and higher daytime dysfunction on trait-level were identified. In addition, several uni-directional associations between loneliness/social connectedness and sleep were found on trait- and state-level. In sum, findings of this study point at a bi-directional relation among loneliness/social connectedness and sleep, in which variables seem to reciprocally influence each other across longer-term periods as well as on a day-to-day basis.

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.

Perceived responsiveness in suicidal ideation: An experience sampling study in psychiatric patients.

INTRODUCTION: Perceived responsiveness, or the extent to which one feels understood, validated and cared for by close others, plays a crucial role in people's well-being. Can this interpersonal process also protect people at risk? We assessed whether fluctuations in suicidal ideation were associated with fluctuations in the degree of perceived responsiveness that psychiatric patients (admitted in the context of suicide or indicating suicidal ideation) experienced in daily interactions immediately after discharge. METHODS: Fifty-seven patients reported on suicidal ideation (5 times a day) and perceived responsiveness (daily) for four consecutive weeks. The effects of established risk factors-thwarted belongingness, perceived burdensomeness, and hopelessness-were assessed as well. RESULTS: The more patients felt that close others had been responsive to them, the less suicidal ideation they reported. At low levels of thwarted belongingness, perceived burdensomeness, or hopelessness, perceived responsiveness seemed to play a protective role, negatively co-occurring with suicidal ideation. When thwarted belongingness, perceived burdensomeness, and hopelessness were high, perceived responsiveness did not have an effect. CONCLUSION: Perceived responsiveness could be a protective factor for suicidal ideation for people at risk only when they are experiencing low levels of negative perceptions. When experiencing highly negative perceptions, however, perceived responsiveness seems to matter less.

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.

Network analyses of ecological momentary emotion and avoidance assessments before and after cognitive behavioral therapy for anxiety disorders.

Negative emotions and associated avoidance behaviors are core symptoms of anxiety. Current treatments aim to resolve dysfunctional coupling between them. However, precise interactions between emotions and avoidance in patients' everyday lives and changes from pre- to post-treatment remain unclear. We analyzed data from a randomized controlled trial where patients with anxiety disorders underwent 16 sessions of cognitive behavioral therapy (CBT). Fifty-six patients (68 % female, age: M = 33.31, SD = 12.45) completed ecological momentary assessments five times a day on 14 consecutive days before and after treatment, rating negative emotions and avoidance behaviors experienced within the past 30 min. We computed multilevel vector autoregressive models to investigate contemporaneous and time-lagged associations between anxiety, depression, anger, and avoidance behaviors within patients, separately at pre- and post-treatment. We examined pre-post changes in network density and avoidance centrality, and related these metrics to changes in symptom severity. Network density significantly decreased from pre- to post-treatment, indicating that after therapy, mutual interactions between negative emotions and avoidance were attenuated. Specifically, contemporaneous associations between anxiety and avoidance observed before CBT were no longer significant at post-treatment. Effects of negative emotions on avoidance assessed at a later time point (avoidance instrength) decreased, but not significantly. Reduction in avoidance instrength positively correlated with reduction in depressive symptom severity, meaning that as patients improved, they were less likely to avoid situations after experiencing negative emotions. Our results elucidate mechanisms of successful CBT observed in patients' daily lives and may help improve and personalize CBT to increase its effectiveness.

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.

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.

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.

Potential therapeutic effects of an ayahuasca-inspired N,N-DMT and harmine formulation: a controlled trial in healthy subjects.

Background: There is growing scientific evidence for the therapeutic benefits of the Amazonian plant-based psychedelic "ayahuasca" for neuropsychiatric disorders such as depression and anxiety. However, there are certain challenges when incorporating botanical ayahuasca into biomedical research and clinical therapy environments. Formulations inspired by ayahuasca, which contain specific and standardized active components, are a potential remedy. Methods: We investigated subjective acute and persisting effects of a novel formulation containing the reversible monoamine oxidase inhibitor harmine (orodispersible tablet containing 100 mg MAO-I) and N,N-dimethyltryptamine (incremental intranasal dosing of up to 100 mg DMT), compared with two other conditions, namely harmine alone and placebo, in a crossover RCT in 31 healthy male subjects. Results: DMT + harmine, but not harmine alone, induced a psychedelic experience assessed with the 5D-ASC rating scale [global score: F(2,60) = 80.21, p < 0.001] and acute experience sampling items over time, characterized by psychological insights [PIQ, F(2,58.5) = 28.514, p < 0.001], emotional breakthroughs [EBI, F(2,60) = 26.509, p < 0.001], and low scores on the challenging experience questionnaire [CEQ, F(2,60) = 12.84, p < 0.001]. Participants attributed personal and spiritual significance to the experience (GSR) with mainly positive persisting effects (PEQ) at 1- and 4-months follow-up. Acute drug effects correlated positively with persisting effects. We found no changes in trait measures of personality, psychological flexibility, or general well-being, and no increases in psychopathology (SCL-90-R) were reported. Discussion and Conclusion: Our results suggest that the experience induced by the standardized DMT + harmine formulation induces a phenomenologically rich psychedelic experience, demonstrates good psychological safety and tolerability, is well tolerated, and induces beneficial psychological processes that could possibly support psychotherapy. Further studies are required to investigate the psychotherapeutic potential in patients.