Inference-Based Cognitive Behavioral Therapy versus Cognitive Behavioral Therapy for Obsessive-Compulsive Disorder: A Multisite Randomized Controlled Non-Inferiority Trial.

INTRODUCTION: Although cognitive behavioral therapy (CBT) effectively treats obsessive-compulsive disorder (OCD), many patients refuse CBT or drop out prematurely, partly because of anxiety regarding exposure and response prevention (ERP) exercises. Inference-based cognitive behavioral therapy (I-CBT) focuses on correcting distorted inferential thinking patterns, enhancing reality-based reasoning, and addressing obsessional doubt by targeting underlying dysfunctional reasoning, without incorporating an ERP component. We hypothesized that I-CBT would be non-inferior to CBT. Additionally, we hypothesized that I-CBT would be more tolerable than CBT. METHODS: 197 participants were randomly assigned to 20 sessions CBT or I-CBT and assessed at baseline, posttreatment, and 6 and 12 months' follow-up. The primary outcome was OCD symptom severity measured using the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS; non-inferiority margin: 2 points). The secondary outcome, treatment tolerability, was assessed using the Treatment Acceptability/Adherence Scale (TAAS). A linear mixed-effects model was used to assess the non-inferiority of the primary outcome and superiority of secondary outcomes. RESULTS: Statistically significant within-group improvements in the primary and secondary outcomes were observed in both treatments. No statistically significant between-group differences in Y-BOCS were found at any assessment point, but the confidence intervals exceeded the non-inferiority threshold, making the results inconclusive. The estimated mean posttreatment TAAS score was significantly higher in the I-CBT group than in the CBT group. CONCLUSION: While both CBT and I-CBT are effective for OCD, whether I-CBT is non-inferior to CBT in terms of OCD symptom severity remains inconclusive. Nevertheless, I-CBT offers better tolerability and warrants consideration as an alternative treatment for OCD.

Imagery rescripting and eye movement desensitisation and reprocessing as treatment for adults with post-traumatic stress disorder from childhood trauma: randomised clinical trial.

BACKGROUND: Investigation of treatments that effectively treat adults with post-traumatic stress disorder from childhood experiences (Ch-PTSD) and are well tolerated by patients is needed to improve outcomes for this population. AIMS: The purpose of this study was to compare the effectiveness of two trauma-focused treatments, imagery rescripting (ImRs) and eye movement desensitisation and reprocessing (EMDR), for treating Ch-PTSD. METHOD: We conducted an international, multicentre, randomised clinical trial, recruiting adults with Ch-PTSD from childhood trauma before 16 years of age. Participants were randomised to treatment condition and assessed by blind raters at multiple time points. Participants received up to 12 90-min sessions of either ImRs or EMDR, biweekly. RESULTS: A total of 155 participants were included in the final intent-to-treat analysis. Drop-out rates were low, at 7.7%. A generalised linear mixed model of repeated measures showed that observer-rated post-traumatic stress disorder (PTSD) symptoms significantly decreased for both ImRs (d = 1.72) and EMDR (d = 1.73) at the 8-week post-treatment assessment. Similar results were seen with secondary outcome measures and self-reported PTSD symptoms. There were no significant differences between the two treatments on any standardised measure at post-treatment and follow-up. CONCLUSIONS: ImRs and EMDR treatments were found to be effective in treating PTSD symptoms arising from childhood trauma, and in reducing other symptoms such as depression, dissociation and trauma-related cognitions. The low drop-out rates suggest that the treatments were well tolerated by participants. The results from this study provide evidence for the use of trauma-focused treatments for Ch-PTSD.

Internet-Based Cognitive Behavioral Therapy for Chronic Fatigue Syndrome Integrated in Routine Clinical Care: Implementation Study.

BACKGROUND: In a clinical trial, internet-based cognitive behavioral therapy (I-CBT) embedded in stepped care was established as noninferior to face-to-face cognitive behavioral therapy (CBT) for chronic fatigue syndrome (CFS). However, treatment effects observed in clinical trials may not necessarily be retained after implementation. OBJECTIVE: This study aimed to investigate whether stepped care for CFS starting with I-CBT, followed by face-to-face CBT, if needed, was also effective in routine clinical care. Another objective was to explore the role of therapists' attitudes toward electronic health (eHealth) and manualized treatment on treatment outcome. METHODS: I-CBT was implemented in five mental health care centers (MHCs) with nine treatment sites throughout the Netherlands. All patients with CFS were offered I-CBT, followed by face-to-face CBT if still severely fatigued or disabled after I-CBT. Outcomes were the Checklist Individual Strength, physical and social functioning (Short-Form 36), and limitations in daily functioning according to the Work and Social Adjustment Scale. The change scores (pre to post stepped care) were compared with a benchmark: stepped care from a randomized controlled trial (RCT) testing this treatment format. We calculated correlations of therapists' attitudes toward manualized treatment and eHealth with reduction of fatigue severity. RESULTS: Overall, 100 CFS patients were referred to the centers. Of them, 79 started with I-CBT, 20 commenced directly with face-to-face CBT, and one did not start at all. After I-CBT, 48 patients met step-up criteria; of them, 11 stepped up to face-to-face CBT. Increase in physical functioning (score of 13.4), social functioning (20.4), and reduction of limitations (10.3) after stepped care delivered in routine clinical care fell within the benchmarks of the RCT (95% CIs: 12.8-17.6; 25.2-7.8; and 7.4-9.8, respectively). Reduction of fatigue severity in the MHCs was smaller (12.6) than in the RCT (95% CI 13.2-16.5). After I-CBT only, reduction of fatigue severity (13.2) fell within the benchmark of I-CBT alone (95% CI 11.1-14.2). Twenty therapists treated between one and 18 patients. Therapists were divided into two groups: one with the largest median reduction of fatigue and one with the smallest. Patients treated by the first group had a significantly larger reduction of fatigue severity (15.7 vs 9.0; t=2.42; P=.02). There were no (statistically significant) correlations between therapists' attitudes and reduction in fatigue. CONCLUSIONS: This study is one of the first to evaluate stepped care with I-CBT as a first step in routine clinical care. Although fatigue severity and disabilities were reduced, reduction of fatigue severity appeared smaller than in the clinical trial. Further development of the treatment should aim at avoiding dropout and encouraging stepping up after I-CBT with limited results. Median reduction of fatigue severity varied largely between therapists. Further research will help understand the role of therapists' attitudes in treatment outcome.

Imagery rescripting and eye movement desensitisation and reprocessing for treatment of adults with childhood trauma-related post-traumatic stress disorder: IREM study design.

BACKGROUND: Post-traumatic stress disorder (PTSD) that originates from childhood trauma experiences can develop into a chronic condition that has lasting effects on an individual's functioning and quality of life. While there are evidence-based guidelines for treating adult onset PTSD, treatments for adults with childhood trauma-related PTSD (Ch-PTSD) are varied and subject to ongoing debate. This study will test the effectiveness of two trauma-focused treatments, imagery rescripting (ImRs) and eye movement desensitisation and reprocessing (EMDR) in participants with Ch-PTSD. Both have been found effective in treatment of adult PTSD or mixed onset PTSD and previous research indicates they are well-tolerated treatments. However, we know less about their effectiveness for treating Ch-PTSD or their underlying working mechanisms. METHODS: IREM is an international multicentre randomised controlled trial involving seven sites across Australia, Germany and the Netherlands. We aim to recruit 142 participants (minimum of n = 20 per site), who will be randomly assigned to treatment condition. Assessments will be conducted before treatment until 1-year follow-up. Assessments before and after the waitlist will assess change in time only. The primary outcome measure is change in PTSD symptom severity from pre-treatment to 8-weeks post-treatment. Secondary outcome measures include change in severity of depression, anger, trauma-related cognitions, guilt, shame, dissociation and quality of life. Underlying mechanisms of treatment will be assessed on changes in vividness, valence and encapsulated belief of a worst trauma memory. Additional sub-studies will include qualitative investigation of treatment experiences from the participant and therapists' perspective, changes in memory and the impact of treatment fidelity on outcome measures. DISCUSSION: The primary aims of this study are to compare the effectiveness of EMDR and ImRs in treating Ch-PTSD and to investigate the underlying working mechanisms of the two treatments. The large-scale international design will make a significant contribution to our understanding of how these treatments address the needs of individuals with Ch-PTSD and therefore, potentially improve their effectiveness. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12614000750684 . Registered 16 July 2014.

The effect of twice-weekly versus once-weekly sessions of either imagery rescripting or eye movement desensitization and reprocessing for adults with PTSD from childhood trauma (IREM-Freq): a study protocol for an international randomized clinical trial.

BACKGROUND: Trauma-focused treatments for posttraumatic stress disorder (PTSD) are commonly delivered either once or twice a week. Initial evidence suggests that session frequency affects treatment response, but very few trials have investigated the effect of session frequency. The present study's aim is to compare treatment outcomes of twice-weekly versus once-weekly sessions of two treatments for PTSD related to childhood trauma, imagery rescripting (ImRs) and eye movement desensitization and reprocessing (EMDR). We hypothesize that both treatments will be more effective when delivered twice than once a week. How session frequency impacts treatment response, whether treatment type moderates the frequency effect, and which treatment type and frequency works best for whom will also be investigated. METHODS: The IREM-Freq trial is an international multicenter randomized clinical trial conducted in mental healthcare centers across Australia, Germany, and the Netherlands. We aim to recruit 220 participants, who will be randomized to one of four conditions: (1) EMDR once a week, (2) EMDR twice a week, (3) ImRs once a week, or (4) ImRs twice a week. Treatment consists of 12 sessions. Data are collected at baseline until one-year follow-up. The primary outcome measure is clinician-rated PTSD symptom severity. Secondary outcome measures include self-reported PTSD symptom severity, complex PTSD symptoms, trauma-related cognitions and emotions, depressive symptoms, dissociation, quality of life, and functioning. Process measures include memory, learning, therapeutic alliance, motivation, reluctance, and avoidance. Additional investigations will focus on predictors of treatment outcome and PTSD severity, change mechanisms of EMDR and ImRs, the role of emotions, cognitions, and memory, the optimization of treatment selection, learned helplessness, perspectives of patients and therapists, the network structure of PTSD symptoms, and sudden treatment gains. DISCUSSION: This study will extend our knowledge on trauma-focused treatments for PTSD related to childhood trauma and, more specifically, the importance of session frequency. More insight into the optimal session frequency could lead to improved treatment outcomes and less dropout, and in turn, to a reduction of healthcare costs. Moreover, the additional investigations will broaden our understanding of how the treatments work and variables that affect treatment outcome. TRIAL REGISTRATION: Netherlands Trial Register NL6965, registered 25/04/2018.

Development and psychometric evaluation of the Transdiagnostic Decision Tool: matched care for patients with a mental disorder in need of highly specialised care.

BACKGROUND: Early identification of patients with mental health problems in need of highly specialised care could enhance the timely provision of appropriate care and improve the clinical and cost-effectiveness of treatment strategies. Recent research on the development and psychometric evaluation of diagnosis-specific decision-support algorithms suggested that the treatment allocation of patients to highly specialised mental healthcare settings may be guided by a core set of transdiagnostic patient factors. AIMS: To develop and psychometrically evaluate a transdiagnostic decision tool to facilitate the uniform assessment of highly specialised mental healthcare need in heterogeneous patient groups. METHOD: The Transdiagnostic Decision Tool was developed based on an analysis of transdiagnostic items of earlier developed diagnosis-specific decision tools. The Transdiagnostic Decision Tool was psychometrically evaluated in 505 patients with a somatic symptom disorder or post-traumatic stress disorder. Feasibility, interrater reliability, convergent validity and criterion validity were assessed. In order to evaluate convergent validity, the five-level EuroQol five-dimensional questionnaire (EQ-5D-5L) and the ICEpop CAPability measure for Adults (ICECAP-A) were administered. RESULTS: The six-item clinician-administered Transdiagnostic Decision Tool demonstrated excellent feasibility and acceptable interrater reliability. Spearman's rank correlations between the Transdiagnostic Decision Tool and ICECAP-A (-0.335), EQ-5D-5L index (-0.386) and EQ-5D-visual analogue scale (-0.348) supported convergent validity. The area under the curve was 0.81 and a cut-off value of ≥3 was found to represent the optimal cut-off value. CONCLUSIONS: The Transdiagnostic Decision Tool demonstrated solid psychometric properties and showed promise as a measure for the early detection of patients in need of highly specialised mental healthcare.

From drought sensing to developmental control: evolution of cyclic AMP signaling in social amoebas.

Amoebas and other protists commonly encyst when faced with environmental stress. Although little is known of the signaling pathways that mediate encystation, the analogous process of spore formation in dictyostelid social amoebas is better understood. In Dictyostelium discoideum, secreted cyclic AMP (cAMP) mediates the aggregation of starving amoebas and induces the differentiation of prespore cells. Intracellular cAMP acting on cAMP-dependent protein kinase (PKA) triggers the maturation of spores and prevents their germination under the prevalent conditions of high osmolality in the spore head. The osmolyte-activated adenylate cyclase, ACG, produces cAMP for prespore differentiation and inhibition of spore germination. To retrace the origin of ACG function, we investigated ACG gene conservation and function in species that span the dictyostelid phylogeny. ACG genes, osmolyte-activated ACG activity, and osmoregulation of spore germination were detected in species that represent the 4 major groups of Dictyostelia. Unlike the derived species D. discoideum, many basal Dictyostelia have retained the ancestral mechanism of encystation from solitary amoebas. In these species and in solitary amoebas, encystation is independently triggered by starvation or by high osmolality. Osmolyte-induced encystation was accompanied by an increase in cAMP and prevented by inhibition of PKA, indicating that ACG and PKA activation mediate this response. We propose that high osmolality signals drought in soil amoebas and that developmental cAMP signaling in the Dictyostelia has evolved from this stress response.

Assessing inpatients' satisfaction with hospital care: should we prefer evaluation or satisfaction ratings?

Inpatients' satisfaction with hospital care is often assessed by questionnaire. From a psychometrical standpoint, this method has drawbacks, however. We further investigated which item response format would maximise desirable outcomes regarding characteristics of the sample obtained (response rate and representativeness) and psychometric properties of the instrument (e.g. missing items responses, variance, validity) as an initial study into this question was indecisive. Subjects were 1184 discharged inpatients, of which 728 patients (62%) responded. They filled out a 55-item satisfaction questionnaire, addressing 12 aspects of care, using either a 10-point Evaluation scale ranging from "very poor" to "excellent" (E10) or a 5-point Satisfaction scale ranging from "dissatisfied" to "very satisfied" (S5). Both E10 and S5 showed good psychometric properties, but S5 yielded a better score distribution. Other results also favoured S5, but differences were small. In conclusion, different response formats do not yield widely different results. Thus, in choosing between them, convenience could be a decisive factor.

Predicting adherence to prophylactic medication in adolescents with asthma: an application of the ASE-model.

An explanatory framework, referred to as the attitude/social influence/self-efficacy-model (ASE-model), was utilised to explain future self-reported adherence of adolescents to daily inhaled prophylactic asthma medication. The objective was to investigate the long-term influence of these earlier reported cognitive variables and other psychological and medical determinants on self-reported adherence 1 year later. Data were collected, via a questionnaire, from 86 adolescents with asthma (aged 11 through 18 years) recruited from outpatient clinics. Adherence was assessed by asking the patients to give themselves a report mark for adherence. The results of the multiple regression analyses showed that the three major ASE-variables were predictors of self-reported adherence to a moderate degree (R(2)=0.21). Previous self-reported adherence was found to be the best predictor of self-reported adherence to prophylactic asthma medication 1 year later (R(2)=0.45). The results of this study could be useful in the development of interventions to enhance adherence to asthma medication. In future, such interventions should focus on feelings of shame about having asthma and promoting healthy habits, such as adherence to medication.

Rac1 and Rac3 have opposing functions in cell adhesion and differentiation of neuronal cells.

Rac1 and Rac3 are highly homologous members of the Rho small GTPase family. Rac1 is ubiquitously expressed and regulates cell adhesion, migration and differentiation in various cell types. Rac3 is primarily expressed in brain and may therefore have a specific function in neuronal cells. We found that depletion of Rac1 by short interference RNA leads to decreased cell-matrix adhesions and cell rounding in neuronal N1E-115 cells. By contrast, depletion of Rac3 induces stronger cell adhesions and dramatically increases the outgrowth of neurite-like protrusions, suggesting opposite functions for Rac1 and Rac3 in neuronal cells. Consistent with this, overexpression of Rac1 induces cell spreading, whereas overexpression of Rac3 results in a contractile round morphology. Rac1 is mainly found at the plasma membrane, whereas Rac3 is predominantly localized in the perinuclear region. Residues 185-187, present in the variable polybasic rich region at the carboxyl terminus are responsible for the difference in phenotype induced by Rac1 and Rac3 as well as for their different intracellular localization. The Rac1-opposing function of Rac3 is not mediated by or dependent on components of the RhoA signaling pathway. It rather seems that Rac3 exerts its function through negatively affecting integrin-mediated cell-matrix adhesions. Together, our data reveal that Rac3 opposes Rac1 in the regulation of cell adhesion and differentiation of neuronal cells.

The Rac exchange factor Tiam1 is required for the establishment and maintenance of cadherin-based adhesions.

Rho family proteins are essential for the formation of adherens junctions, which are required for the maintenance of epithelial integrity. Activated Rac and the Rac exchange factor Tiam1 have been shown to promote the formation of adherens junctions and the accompanying induction of an epithelioid phenotype in a number of cell lines. Here we show that Madin-Darby canine kidney II cells in which Tiam1 was down-regulated using short interfering RNA disassembled their cadherin-based adhesions and acquired a flattened, migratory, and mesenchymal morphology. In addition, the expression of E1A in mesenchymal V12Ras-transformed Madin-Darby canine kidney II cells led simultaneously to the up-regulation of the Tiam1 protein, the activation of Rac, the formation of cadherin-based adhesions, and reversion to an epithelial phenotype. This finding suggests that E1A induces an epithelial morphology through the up-regulation of Tiam1 and, thereby, the activation of Rac and the formation of cadherin-based adhesions. Indeed, we found that E1A is able to induce an epithelial-like morphology accompanied by the formation of cadherin-based adhesions only in wild-type but not in Tiam1-deficient primary mouse embryonic fibroblasts. These studies indicate that the Rac activator Tiam1 is essential for the formation as well as the maintenance of cadherin-based adhesions.

High cAMP in spores of Dictyostelium discoideum: association with spore dormancy and inhibition of germination.

Signalling mechanisms involving cAMP have a well-documented role in the coordination of multicellular development and differentiation leading to spore formation in the social amoeba, Dictyostelium discoideum. The involvement of cAMP in the poorly understood developmental stages of spore dormancy and germination have been investigated in this study. Dormant spores contained up to 11-fold more cAMP than nascent amoebae. The spore cAMP levels were not constant, but typically underwent a surge at 14-18 d when spores acquired the ability to germinate spontaneously. The high cAMP levels decreased only during successful spore germination, i.e. emergence of nascent amoebae. The temporal pattern of cAMP decrease was complex and unique to the method of spore activation, supporting our hypothesis that exogenously (e.g. heat) activated and autoactivated spores germinate by different mechanisms. During heat-induced activation, transcription of acg (a gene encoding adenylyl cyclase associated with germination) correlated well with spore cAMP content. Young wild-type spores, incapable of spontaneous germination, maintained a uniformly high cAMP level, and spore cAMP levels also remained high if germination was inhibited. When activated spores were deactivated by applying increased osmotic pressure, cAMP concentrations rose and ultimately levelled off at the high levels typical of dormant spores. The correlation between high cAMP and failure to germinate was also evident when autoactivation was inhibited by the cAMP analogue, 8-bromo-cAMP. Also, spores from a strain (HTY217) with unrestrained protein kinase A activity were incapable of spontaneous germination. Overall, our experiments provide evidence for continued cAMP signalling in spores up to 18 d after sporulation and for linkages between elevated cAMP, spore deactivation and inhibition of spontaneous germination.