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ABSTRACT: Subthreshold anxiety and subthreshold depressive symptoms often co-occur in the general population and in primary care. Based on their associated significant distress and impairment, a psychiatric classification seems justified. To enable classification, mixed anxiety depression (MAD) has been proposed as a new diagnostic category in DSM-5. In this report, we discuss arguments against the classification of MAD. More research is needed before reifying a new category we know so little about. Moreover, we argue that in patients with MAD symptoms and a history of an anxiety or depressive disorder, symptoms should be labeled as part of the course trajectories of these disorders, rather than calling it a different diagnostic entity. In patients with incident co-occurring subthreshold anxiety and subthreshold depression, subthreshold categories of both anxiety and depression could be classified to maintain a consistent classification system at both threshold and subthreshold levels. [ABSTRACT FROM AUTHOR]

Background: Risk factors of a chronic course of anxiety and depressive disorders were previously studied using a limited definition of recovery, i.e. remission of the index disorder. However, frequently, other mental disorders are present at follow-up. Thus, the course of anxiety and depressive disorders was represented too rosy and the identified determinants may not apply when using a broader, more realistic definition. Additionally, physical health risk factors have often been ignored., Methods: Data were used from two waves of the Netherlands Mental Health Survey and Incidence Study-2 including 509 respondents with 12-month anxiety disorder (panic disorder, social phobia, agoraphobia or generalized anxiety disorder) or/and major depressive disorder at baseline. Chronic course was defined as (1) presence of index disorder; and (2) presence of any anxiety, mood or substance use disorder (overall course) during the subsequent three years. Regression models were built with sociodemographic, clinical, and lifestyle/physical health indicators. Predictive accuracy was evaluated with area under the curve (AUC)., Results: Chronic course of the index disorder was present among 24.8% of cases, whereas 38.7% had a chronic overall course. The accuracy of prediction of chronic course of the index disorder was suboptimal (AUC = 0.68) compared to prediction of overall course (AUC = 0.75). The main risk factors were baseline number of mental disorders, neuroticism, childhood abuse, parental psychopathology and alcohol use. Lifestyle and physical health indicators were marginally relevant., Conclusion: Transdiagnostic risk factors are important in predicting overall course of anxiety and depressive disorders but cannot accurately predict chronic course of the index disorder., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Background: Repetitive transcranial magnetic stimulation (rTMS) is an emerging treatment for obsessive-compulsive disorder (OCD). The neurobiological mechanisms of rTMS in OCD have been incompletely characterized. We compared clinical outcomes and changes in task-based brain activation following three different rTMS stimulation protocols, all combined with exposure and response prevention (ERP)., Methods: In this three-arm proof-of-concept randomized trial, 61 treatment-refractory adult OCD patients received 16 sessions of rTMS immediately prior to ERP over 8 weeks, with task-based functional MRI (tb-fMRI) scans and clinical assessments pre- and post-treatment. Patients received either: high frequency (HF) rTMS to the left dorsolateral prefrontal cortex (DLPFC)(n=19(6M/13F)); HF rTMS to the left pre-supplementary motor area (preSMA)(n=23(10M/13F)); or control rTMS to the vertex(n=19(6M/13F)). Changes in tb-fMRI activation pre-post treatment were compared using both a Bayesian region-of-interest and a general linear model whole-brain approach., Results: Mean OCD symptom severity decreased significantly in all treatment groups (delta=-10.836, p<0.001, 95% CI[-12.504,-9.168]), with no differences between groups. Response rate in the entire sample was 57.4%. The DLPFC rTMS group showed decreased planning-related activation post-treatment that was associated with greater symptom improvement. No group-level activation changes were observed for the preSMA or vertex rTMS groups. Participants with greater symptom improvement in the preSMA group showed decreased error-related activation, and symptom improvement in the vertex group was associated with increased inhibition-related activation., Conclusions: PreSMA and DLPFC rTMS combined with ERP led to activation decreases in targeted task networks in individuals showing greater symptom improvement, although we observed no differences in symptom reduction between groups., (Copyright © 2024. Published by Elsevier Inc.)

Objective: To test a multifaceted treatment program for patients with obsessive-compulsive disorder (OCD) who did not respond to regular cognitive behavior therapy (CBT). The treatment addresses several factors that may play a role in maintaining OCD., Methods: We designed a treatment consisting of a 6-day intensive, individual exposure in vivo with response prevention (ERP) format, with 24 therapist-assisted treatment hours at the patient's home and 12 self-controlled ERP hours, including behavioral activation and family interventions. Next, we investigated the effect (obsessive-compulsive symptoms, comorbidity, functioning, quality of life, OCD-related interaction patterns) and feasibility (dropout, treatment satisfaction, and organization) of this program using pre-post-tests, pre-follow-up tests, and qualitative data from patients, family members, and therapists., Results: In a sample of 22 participants, obsessive-compulsive symptoms (Y-BOCS pre: 28.7, post: 15.9; Wilcoxon S-R tests P<0.01) improved significantly, as did most other effect measures. Results were largely, but not completely, preserved at 3-month follow-up. There was only 1 dropout. Patients, family members, and therapists were satisfied with the treatment. Implementation of the treatment did not pose difficulties., Conclusions: In nonresponders with OCD, a multifaceted, brief, intensive home-based ERP program targeting factors maintaining OCD is promising and feasible. Extra care is needed to maintain improvement., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Depression in adolescents and young adults is common and causes considerable disease burden while hampering their development, leading to adverse consequences in later life. Although treatment is available, young people are a vulnerable group regarding uptake and completion of treatment. To improve this, insight into youth's preferences for treatment is essential., Objective: The aim of this study was to investigate patient preferences for depression treatment in a Dutch sample aged 16-24 years using a discrete choice experiment (DCE)., Methods: The study was conducted in The Netherlands between October 2018 and June 2019, and included 236 adolescents and young adults with current depressive symptoms or previous treatment. The DCE included five attributes (treatment type, frequency of appointment, waiting time, effectiveness, evaluation of therapeutic alliance) with corresponding levels. Results were analysed using latent class analysis., Results: Results show a general preference for individual psychotherapy, treatment with high frequency, high effectiveness, short waiting time and a standard evaluation of the therapeutic alliance ('click' with the therapist) early in treatment. Latent class analysis revealed three different patterns of preferences regarding treatment type and willingness to engage in therapy. The first class showed a strong preference for individual therapy. The second class, including relatively older, higher educated and treatment-experienced participants, preferred high frequency treatment and was more open to different forms of therapy. The third class, including lower educated, younger and treatment-naïve adolescents showed reluctance to engage in therapy overall and in group therapy specifically., Conclusion: In this DCE, three classes could be identified that share similar preferences regarding treatment effectiveness, waiting time and evaluation of the therapeutic alliance, but varied considerably in their preference for treatment type (individual, group, or combined psychotherapy) and their willingness to engage. The results from this study may inform mental health care providers and institutions and help optimize professional care for adolescents and young adults with depressive symptoms, improving engagement in this vulnerable group., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background: Taking patient preference into consideration has received increased attention in the last decades. We conducted a meta-analysis to estimate the effects of patient preference on clinical outcome, satisfaction and adherence regarding treatment of depression and anxiety., Methods: Pubmed, Embase, PsycINFO and Scopus were searched for (cluster) randomized controlled trials. Twenty-six randomized controlled clinical trials were included, comprising 3670 participants, examining the effect of patient preference regarding treatment of anxiety and depression on clinical outcome, satisfaction and/or adherence., Results: No effect of patient preference was found on clinical outcome [d = 0.06, 95% CI = (-0.03, 0.15), p = 0.16, n = 23 studies]. A small effect of patient preference was found on treatment satisfaction [d = 0.33, 95% CI = (0.08, 0.59), p = 0.01, n = 6 studies] and on treatment adherence [OR = 1.55, 95% CI = (1.28, 1.87), p < 0.001, n = 22 studies]., Limitations: Patient preference is a heterogeneous concept, future studies should strive to equalize operationalization of preference. Subgroup analyses within this study should be interpreted with caution because the amount of studies per analysed subgroup was generally low. Most studies included in this meta-analysis focused on patients with depression. The small number of studies (n = 6) on satisfaction, prevents us from drawing firm conclusions., Conclusions: While this meta-analysis did not find a positive effect of considering patient preference on clinical outcome, it was associated with slightly better treatment satisfaction and adherence. Accommodating preference of patients with anxiety and depression can improve treatment., Trial Registration: PROSPERO: CRD42020172556., (© 2024 The Authors. Clinical Psychology & Psychotherapy published by John Wiley & Sons Ltd.)

Anxiety disorders are very prevalent and often persistent mental disorders, with a considerable rate of treatment resistance which requires regulatory clinical trials of innovative therapeutic interventions. However, an explicit definition of treatment-resistant anxiety disorders (TR-AD) informing such trials is currently lacking. We used a Delphi method-based consensus approach to provide internationally agreed, consistent and clinically useful operational criteria for TR-AD in adults. Following a summary of the current state of knowledge based on international guidelines and an available systematic review, a survey of free-text responses to a 29-item questionnaire on relevant aspects of TR-AD, and an online consensus meeting, a panel of 36 multidisciplinary international experts and stakeholders voted anonymously on written statements in three survey rounds. Consensus was defined as ≥75% of the panel agreeing with a statement. The panel agreed on a set of 14 recommendations for the definition of TR-AD, providing detailed operational criteria for resistance to pharmacological and/or psychotherapeutic treatment, as well as a potential staging model. The panel also evaluated further aspects regarding epidemiological subgroups, comorbidities and biographical factors, the terminology of TR-AD vs. "difficult-to-treat" anxiety disorders, preferences and attitudes of persons with these disorders, and future research directions. This Delphi method-based consensus on operational criteria for TR-AD is expected to serve as a systematic, consistent and practical clinical guideline to aid in designing future mechanistic studies and facilitate clinical trials for regulatory purposes. This effort could ultimately lead to the development of more effective evidence-based stepped-care treatment algorithms for patients with anxiety disorders., (© 2024 World Psychiatric Association.)

Insomnia is common throughout the population and thought to be a risk factor for mental disorders. We assessed the association of insomnia symptoms with incidence, recurrence and persistence of mood, anxiety and substance use disorders. In 4007 participants (55 % women, mean age 51.0 ± 12.3) of the population-based Netherlands Mental Health Survey and Incidence Study (NEMESIS), having insomnia symptoms increased the odds of developing, recurring and persisting mood disorders, mostly in men. Insomnia only associated with recurring anxiety disorders, particularly in women, and not with substance use disorders. Treating insomnia may aid recovery and prevention of mental disorders, particularly mood disorders., Competing Interests: Declaration of Competing Interest The authors have no conflict of interest., (Copyright © 2023. Published by Elsevier B.V.)

Dropout from psychological or pharmacological treatment for anxiety and depressive disorders is common. It is especially problematic in adolescents and young adults because of the adverse consequences for their development. Reasons for treatment dropout can be divided into therapy-process related factors, attitudinal aspects, and practical issues. Adjusting treatment to patient preferences and shared decision making, improving the therapeutic alliance, and interventions such as (family) psychoeducation, motivational interviewing, and help with practical issues are promising strategies to optimize engagement and adherence., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Waumans, Muntingh, Batelaan and van Balkom.)

Background: Antidepressant medication and running therapy are both effective treatments for patients with depressive and anxiety disorders. However, they may work through different pathophysiological mechanisms and could differ in their impact on physical health. This study examined effects of antidepressants versus running therapy on both mental and physical health., Methods: According to a partially randomized patient preference design, 141 patients with depression and/or anxiety disorder were randomized or offered preferred 16-week treatment: antidepressant medication (escitalopram or sertraline) or group-based running therapy ≥2 per week. Baseline (T0) and post-treatment assessment at week 16 (T16) included mental (diagnosis status and symptom severity) and physical health indicators (metabolic and immune indicators, heart rate (variability), weight, lung function, hand grip strength, fitness)., Results: Of the 141 participants (mean age 38.2 years; 58.2 % female), 45 participants received antidepressant medication and 96 underwent running therapy. Intention-to-treat analyses showed that remission rates at T16 were comparable (antidepressants: 44.8 %; running: 43.3 %; p = .881). However, the groups differed significantly on various changes in physical health: weight (d = 0.57; p = .001), waist circumference (d = 0.44; p = .011), systolic (d = 0.45; p = .011) and diastolic (d = 0.53; p = .002) blood pressure, heart rate (d = 0.36; p = .033) and heart rate variability (d = 0.48; p = .006)., Limitations: A minority of the participants was willing to be randomized; the running therapy was larger due to greater preference for this intervention., Conclusions: While the interventions had comparable effects on mental health, running therapy outperformed antidepressants on physical health, due to both larger improvements in the running therapy group as well as larger deterioration in the antidepressant group., Trial Registration: Trialregister.nl Number of identification: NTR3460., Competing Interests: Conflict of interest All authors declare no conflict of interest., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Borderline personality disorder (BPD) has a negative impact on the onset and course of anxiety disorders. However, even though many people with anxiety disorders only have some BPD symptoms, little is known about the impact of BPD symptoms on anxiety disorders. This study examines the impact of BPD symptoms on the onset and persistence of anxiety disorders over a 3-year follow-up in the general population. Longitudinal data from the Netherlands Mental Health Survey and Incidence study were used ( N = 4,618). BPD symptoms were assessed using the International Personality Examination, and anxiety disorders and other mental disorders were assessed with the Composite International Diagnostic Interview. Logistic regression analyses were performed, adjusting for a wide range of potential confounders such as childhood abuse and mood disorders. In all, 72.1% of the participants reported no BPD symptoms, 24.0% reported one to two symptoms, 3.1% reported three to four symptoms, and 0.8% reported ≥ 5 symptoms. There was a clear dose-response relation, with more BPD symptoms being associated with a higher risk for onset and persistence of anxiety disorders (both p for trend < .001). Even one to two BPD symptoms significantly impacted the onset (odds ratio = 3.32, 95% confidence interval [1.68, 6.54]) and persistence (odds ratio = 3.12, 95% confidence interval [1.01, 9.64]). Results appeared to be independent of multiple potential confounders. Even a low number of BPD symptoms impact the onset and persistence of anxiety disorders. Targeting these symptoms may improve the outcome of anxiety disorders. Future research should study the effect of various interventions for people with anxiety disorders and BPD symptoms. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Background: Insomnia is the transdiagnostically shared most common complaint in disorders of anxiety, stress and emotion regulation. Current cognitive behavioral therapies (CBT) for these disorders do not address sleep, while good sleep is essential for regulating emotions and learning new cognitions and behaviours: the core fundaments of CBT. This transdiagnostic randomized control trial (RCT) evaluates whether guided internet-delivered cognitive behavioral therapy for insomnia (iCBT-I) (1) improves sleep, (2) affects the progression of emotional distress and (3) enhances the effectiveness of regular treatment of people with clinically relevant symptoms of emotional disorders across all mental health care (MHC) echelons., Methods: We aim for 576 completers with clinically relevant symptoms of insomnia as well as at least one of the dimensions of generalized anxiety disorder (GAD), social anxiety disorder (SAD), panic disorder (PD), posttraumatic stress disorder (PTSD) or borderline personality disorder (BPD). Participants are either pre-clinical, unattended, or referred to general- or specialized MHC. Using covariate-adaptive randomization, participants will be assigned to a 5 to 8-week iCBT-I (i-Sleep) or a control condition (sleep diary only) and assessed at baseline, and after two and eight months. The primary outcome is insomnia severity. Secondary outcomes address sleep, severity of mental health symptoms, daytime functioning, mental health protective lifestyles, well-being, and process evaluation measures. Analyses use linear mixed-effect regression models., Discussion: This study can reveal for whom, and at which stage of disease progression, better nights could mean substantially better days., Trial Registration: International Clinical Trial Registry Platform (NL9776). Registered on 2021-10-07., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: AVS and JLa cowrote the i-Sleep intervention but have no commercial nor financial interests in it. All other authors declare that they have no known competing financial interests of personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Treatment resistance in patients with anxiety disorders and obsessive-compulsive disorder (OCD) might be caused by dysfunctional personality traits or, more specifically, early maladaptive schemas (EMSs) and schema modes, that can be treated with schema therapy (ST)., Aim: To explore possible effectiveness of ST-CBT day-treatment in patients with treatment-resistant anxiety disorders and OCD in an uncontrolled pilot study., Method: Treatment-resistant patients with anxiety disorders or OCD ( n = 27) were treated with ST-CBT day-treatment for 37 weeks on average including 11.5 therapy hours per week. The Symptom Questionnaire-48, Young Schema Questionnaire-2 and Schema Mode Inventory were completed before and after treatment., Results: General psychopathology, EMSs and schema modes significantly improved after treatment. Spearman's correlations between pre- to post-treatment difference scores of general psychopathology, EMSs and schema modes were significant and high. The level of pre-treatment EMSs and schema modes did not predict post-treatment general psychopathology., Conclusions: Symptom reduction was strongly correlated with improvement of EMSs and schema modes. Stronger pre-treatment EMSs and schema modes did not hinder improvement of symptoms. ST-CBT day-treatment is promising for patients with treatment-resistant anxiety disorders and OCD. Further controlled research is needed to substantiate evidence for schema therapy in patients with treatment-resistant anxiety disorders and OCD.

Background: Sleep gets little attention in mental health care treatments. Epidemiological research with regards to the association between sleep problems and anxiety and mood disorders can contribute to good clinical decision making., Aim: Based on data from the Netherlands Mental Health Survey and Incidence Study-2 (NEMESIS-2), we examined the relation between sleep problems and first onset, recurrence and persistence of anxiety and mood disorders within a 3 year period., Method: Different groups of respondents were selected to examine the relation between sleep problems and different stages of anxiety and mood disorders within three years. DSM-IV diagnoses were determined using the Composite International Diagnostic Interview (CIDI 3.0) and sleep problems with the Women&rsquo;s Health Initiative Insomnia Rating Scale (IRS; &ge; 9). Logistic regression was performed. Multivariable analysis took into account a large number of potentially confounding variables., Results: Almost a quarter of the respondents without an anxiety or mood disorder and almost half of the respondents with an anxiety or mood disorder experience sleep problems. In the multivariable analysis, sleep problems were associated with recurrence of an anxiety disorder (OR 2.10; 95% CI 1.31-3.38), but not with the first onset and persistence of an anxiety disorder. Furthermore, sleep problems appear to be associated with the first onset of a mood disorder (OR 2.18; 95% CI 1.27-3.74) and with the persistence of a mood disorder (OR 2.51; 95% CI 1.17-5.37), but not with recurrence of this disorder., Conclusion: The results underline the importance of identifying sleep problems of people with (an increased risk of) anxiety and mood disorders. The treatment of sleep problems may contribute to a reduced incidence of these mental disorders and a better and sustainable recovery.

Background: Shared decision making (SDM) is advised in the treatment guideline for depressive disorders. However, it&rsquo;s unclear if SDM contributes to the optimization of care., Aim: To provide an overview of the effects of SDM within the treatment of depression on treatment outcome, patient satisfaction and adherence through a meta-analysis and systematic review., Method: In a literature search (PubMed, PsycINFO, Embase), randomised controlled studies with patients who suffer from depression or depressive symptoms were selected. The effect of a SDM intervention previous to treatment was compared to no SDM intervention on the outcome measures. Effect sizes were computed with random effects models and risk of bias was assessed., Results: Five studies were included (N = 850). SDM did not result in superior treatment outcome (Cohen&rsquo;s d = 0.02; , 95%-BI:-0.12-0,16; p = 0.773) and adherence (Cohen&rsquo;s d = 0.29; 95%-BI:-0.01-0.58; p = 0.056). SDM did lead to higher patient satisfaction with a medium-large effect size (Cohen&rsquo;s d = 0.53; 95%-BI:0,17-0.90; p = .004)., Conclusion: SDM resulted in higher patient satisfaction, no effects were found regarding treatment outcome and adherence. However, operationalisation of SDM in the studies were variable. SDM appears to be a versatile construct in clinical practice.

Background: Existing studies on disease course usually apply relatively short follow-up periods and narrow definitions of disease course resulting in too optimistic views on disease prognosis. This study explores the relevance of using a longer and broader (cross-disorder) perspective., Methods: Respondents with a 12-month disorder at baseline and available at 3-, 6- and 9-year follow-up were selected (major depressive disorder, MDD: n = 208; anxiety disorder: n = 220) from a general population study (N = 6646). DSM-IV disorders were assessed with the Composite International Diagnostic Interview. Disease course was described using a short and narrow perspective (i.e., 3-year follow-up, and considering presence of the index disorder only) and a long and broad perspective (9-year follow-up, and considering presence of any mood, anxiety or substance use disorder as outcome)., Results: The recovery rates of both MDD and anxiety disorder reduced by half when the perspective switched from short and narrow (MDD: 74.0 %; anxiety disorder: 79.5 %) to long and broad (35.6 % and 40.0 % respectively). At 9-year follow-up, the rates of a persistent disorder (a disorder at each follow-up assessment) tripled when the perspective switched from narrow to broad (MDD: from 4.8 % to 13.9 %; anxiety disorder: from 4.5 % to 15.5 %)., Limitations: The findings are not generalizable to the most severe depressed and anxious patients., Conclusions: Most people with MDD or anxiety disorder in the general population have a rather favourable prognosis when a narrow perspective is applied, but an unfavourable prognosis when a long-term and broad perspective is applied. Consequently, MDD and anxiety disorder should not merely be perceived as episodic disorders, and require longer-term disease monitoring and management., Competing Interests: Declaration of competing interest All authors declare that they have no competing interests., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Anxiety disorders (AD) and alcohol use disorder (AUD) frequently co-occur, but the temporal order of the association is unclear. We have determined the association between AD and the presence and first-onset of AUD, and vice versa., Methods: Data were used from n = 6.646 participants and four measurement waves (baseline, 3-, 6- and 9-years) of the Netherlands Mental Health Survey and Incidence Study 2 (NEMESIS-2), a cohort study of the Dutch general population aged 18-64 years. AD and AUD were assessed with the Composite International Diagnostic Interview 3.0. Multilevel logistic autoregressive models were controlled for previous-wave AD or AUD, sociodemographics (Model 1), smoking and clinical factors (Model 2)., Results: People with AUD had a higher risk of present (OR = 1.65, 95 % CI 1.11-2.43; Model 2) and first-onset (OR = 2.03, 95 % CI 1.17-3.51; Model 2) AD in 3-years follow-up intervals than people without AUD. Vice versa, people with AD also had a higher sociodemographics-adjusted risk of present and first-onset AUD over 3-years follow-up intervals, but these associations attenuated into insignificance after adjustment for smoking and clinical variables. Limitations For statistical power reasons we were not able to analyze 9-year follow-up data or distinguish between AD and AUD types., Conclusions: Our results indicate a bidirectional relationship between AD and AUD; especially those with severe AD (medication use, comorbid depression) are at risk of developing AUD. Health care professionals should focus on prevention of AD in AUD patients and prevention of AUD in patients with (more severe) AD. Further research should investigate the mechanisms underlying the observed associations., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Preclinical research suggests that enhancing CB1 receptor agonism may improve fear extinction. In order to translate this knowledge into a clinical application we examined whether cannabidiol (CBD), a hydrolysis inhibitor of the endogenous CB1 receptor agonist anandamide (AEA), would enhance the effects of exposure therapy in treatment refractory patients with anxiety disorders. Patients with panic disorder with agoraphobia or social anxiety disorder were recruited for a double-blind parallel randomised controlled trial at three mental health care centres in the Netherlands. Eight therapist-assisted exposure in vivo sessions (weekly, outpatient) were augmented with 300 mg oral CBD (n = 39) or placebo (n = 41). The Fear Questionnaire (FQ) was assessed at baseline, mid- and post-treatment, and at 3 and 6 months follow-up. Primary analyses were on an intent-to-treat basis. No differences were found in treatment outcome over time between CBD and placebo on FQ scores, neither across (β = 0.32, 95% CI [-0.60; 1.25]) nor within diagnosis groups (β = -0.11, 95% CI [-1.62; 1.40]). In contrast to our hypotheses, CBD augmentation did not enhance early treatment response, within-session fear extinction or extinction learning. Incidence of adverse effects was equal in the CBD (n = 4, 10.3%) and placebo condition (n = 6, 15.4%). In this first clinical trial examining CBD as an adjunctive therapy in anxiety disorders, CBD did not improve treatment outcome. Future clinical trials may investigate different dosage regimens., Competing Interests: Declaration of Competing Interest All authors report no biomedical financial interests or potential conflicts of interest., (Copyright © 2022. Published by Elsevier B.V.)

Background: Given that relapse is common in patients in remission from anxiety and depressive disorders, relapse prevention is needed in the maintenance phase. Although existing psychological relapse prevention interventions have proven to be effective, they are not explicitly based on patients' preferences. Hence, we developed a blended relapse prevention program based on patients' preferences, which was delivered in primary care practices by mental health professionals (MHPs). This program comprises contact with MHPs, completion of core and optional online modules (including a relapse prevention plan), and keeping a mood and anxiety diary in which patients can monitor their symptoms., Objective: The aims of this study were to provide insight into (1) usage intensity of the program (over time), (2) the course of symptoms during the 9 months of the study, and (3) the association between usage intensity and the course of symptoms., Methods: The Guided E-healTh for RElapse prevention in Anxiety and Depression (GET READY) program was guided by 54 MHPs working in primary care practices. Patients in remission from anxiety and depressive disorders were included. Demographic and clinical characteristics, including anxiety and depressive symptoms, were collected via questionnaires at baseline and after 3, 6, and 9 months. Log data were collected to assess the usage intensity of the program., Results: A total of 113 patients participated in the study. Twenty-seven patients (23.9%) met the criteria for the minimal usage intensity measure. The core modules were used by ≥70% of the patients, while the optional modules were used by <40% of the patients. Usage decreased quickly over time. Anxiety and depressive symptoms remained stable across the total sample; a minority of 15% (12/79) of patients experienced a relapse in their anxiety symptoms, while 10% (8/79) experienced a relapse in their depressive symptoms. Generalized estimating equations analysis indicated a significant association between more frequent face-to-face contact with the MHPs and an increase in both anxiety symptoms (β=.84, 95% CI .39-1.29) and depressive symptoms (β=1.12, 95% CI 0.45-1.79). Diary entries and the number of completed modules were not significantly associated with the course of symptoms., Conclusions: Although the core modules of the GET READY program were used by most of the patients and all patients saw an MHP at least once, usage decreased quickly over time. Most patients remained stable while participating in the study. The significant association between the frequency of contact and the course of symptoms most likely indicates that those who received more support had more symptoms, and thus, it is questionable whether the support offered by the program was sufficient to prevent these patients from relapsing., International Registered Report Identifier (irrid): RR2-10.1186/s12888-019-2034-6., (©Esther Krijnen-de Bruin, Anna DT Muntingh, Evelien M Bourguignon, Adriaan Hoogendoorn, Otto R Maarsingh, Anton JLM van Balkom, Neeltje M Batelaan, Annemieke van Straten, Berno van Meijel. Originally published in JMIR Mental Health (https://mental.jmir.org), 16.03.2022.)

Background: Previous research on barriers and facilitators regarding treatment-seeking of adults with depressive and anxiety disorders has been primarily conducted in the Anglosphere. This study aims to gain insight into treatment-seeking behaviour of adults with depressive and anxiety disorders in a European healthcare system., Methods: In-depth semi-structured interviews were conducted with 24 participants, aged ≥18 years and diagnosed with an anxiety disorder and/or depressive disorder according to DSM-IV. Participants were purposively sampled from an outpatient department for mental health care in the Netherlands. The seven steps of framework analysis were used to identify relevant themes emerging from the interviews., Results: Data analysis suggested an interplay between individual aspects, personal social system, healthcare system and sociocultural context influences. Amongst the most relevant themes were mental health illiteracy, stigma, a negative attitude toward professional help, the influence of significant others and general practitioner, and waiting time. Financial barriers were not of relevance., Conclusions: Even in a country with a well-developed mental health care system and in absence of financial barriers, there are many barriers to treatment-seeking in adult patients with depressive and anxiety disorders. National campaigns to increase awareness and decrease stigma in the general population, and to empower the social environment might reduce the treatment gap., (© 2022. The Author(s).)

Sudden cardiac arrest (SCA) is a leading cause of mortality and morbidity in affluent societies, which underscores the need to identify persons at risk. The etiology of SCA is however complex, with predisposing and precipitating factors interacting. Although anxiety and mental stress have been linked to SCA for decades, their precise role and impact remain unclear and the biological underpinnings are insufficiently understood. In this paper, we systematically reviewed various types of observational studies (total n = 20) examining the association between anxiety or mental stress and SCA. Multiple methodological considerations challenged the summarizing and interpretation of the findings. For anxiety, the overall picture suggests that it predisposes for SCA in physically healthy populations (unadjusted OR = 2.44; 95% CI: 1.06-5.59; n = 3). However, in populations at risk for SCA ( n = 4), associations were heterogeneous but not significant. Anxiety may partly predispose to SCA by contributing to other risk factors such as cardiovascular disease and diabetes mellitus via mechanisms such as unhealthy lifestyle and metabolic abnormalities. Mental stress appears to precipitate SCA, presumably by more directly impacting on the cardiac ion channels that control the heart's electrical properties. This may lead to ventricular fibrillation, the arrhythmia that underlies SCA. To advance this field of research, experimental studies that unravel the underlying biological mechanisms are deemed important, and most easily designed for mental stress as a precipitating factor because of the short timeframe. These proof-of-concept studies should examine the whole pathway from the brain to the autonomic nervous system, and eventually to cardiac ion channels. Ultimately, such studies may facilitate the identification of persons at risk and the development of novel preventive strategies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Batelaan, Seldenrijk, van den Heuvel, van Balkom, Kaiser, Reneman and Tan.)

Background: Disease trajectories of patients with anxiety disorders are highly diverse and approximately 60% remain chronically ill. The ability to predict disease course in individual patients would enable personalized management of these patients. This study aimed to predict recovery from anxiety disorders within 2 years applying a machine learning approach., Methods: In total, 887 patients with anxiety disorders (panic disorder, generalized anxiety disorder, agoraphobia, or social phobia) were selected from a naturalistic cohort study. A wide array of baseline predictors ( N = 569) from five domains (clinical, psychological, sociodemographic, biological, lifestyle) were used to predict recovery from anxiety disorders and recovery from all common mental disorders (CMDs: anxiety disorders, major depressive disorder, dysthymia, or alcohol dependency) at 2-year follow-up using random forest classifiers (RFCs)., Results: At follow-up, 484 patients (54.6%) had recovered from anxiety disorders. RFCs achieved a cross-validated area-under-the-receiving-operator-characteristic-curve (AUC) of 0.67 when using the combination of all predictor domains (sensitivity: 62.0%, specificity 62.8%) for predicting recovery from anxiety disorders. Classification of recovery from CMDs yielded an AUC of 0.70 (sensitivity: 64.6%, specificity: 62.3%) when using all domains. In both cases, the clinical domain alone provided comparable performances. Feature analysis showed that prediction of recovery from anxiety disorders was primarily driven by anxiety features, whereas recovery from CMDs was primarily driven by depression features., Conclusions: The current study showed moderate performance in predicting recovery from anxiety disorders over a 2-year follow-up for individual patients and indicates that anxiety features are most indicative for anxiety improvement and depression features for improvement in general.

Objective: To examine the underlying factor structure and psychometric properties of the Assessment of Self-management in Anxiety and Depression (ASAD) questionnaire, which was specifically designed for patients with (chronic) anxiety and depressive disorders. Moreover, this study assesses whether the number of items in the ASAD can be reduced without significantly reducing its precision. Methods: The ASAD questionnaire was completed by 171 participants across two samples: one sample comprised patients with residual anxiety or depressive symptoms, while the other consisted of patients who have been formally diagnosed with a chronic anxiety or depressive disorder. All participants had previously undergone treatment. Both exploratory (EFA) and confirmatory factor analyses (CFA) were conducted. Internal consistency and test-retest reliability were also assessed. Results: Both EFA and CFA indicated three solid factors: Seeking support, Daily life strategies and Taking ownership [Comparative Fit Index = 0.80, Tucker Lewis Index = 0.78, Root Mean Square Error of Approximation = 0.09 (CI 0.08-1.00), Standardized Root Mean Square Residual = 0.09 (χ 2 = 439.35, df = 168)]. The ASAD was thus reduced from 45 items to 21 items, which resulted in the ASAD-Short Form (SF). All sub-scales had a high level of internal consistency (> α = 0.75) and test-retest reliability (ICC > 0.75). Discussion: The first statistical evaluation of the ASAD indicated a high level of internal consistency and test-retest reliability, and identified three distinctive factors. This could aid patients and professionals' assessment of types of self-management used by the patient. Given that this study indicated that the 21-item ASAD-SF is appropriate, this version should be further explored and validated among a sample of patients with (chronic or partially remitted) anxiety and depressive disorders. Alongside this, to increase generalizability, more studies are required to examine the English version of the ASAD within other settings and countries., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Krijnen-de Bruin, Draisma, Muntingh, Evers, van Straten, Sinnema, Spijker, Batelaan and van Meijel.)

Objective: Little is known about the course of anxiety disorders in the general population. This study provides insights into the course of anxiety disorders in the general population taking into account transition to residual symptoms and to other diagnostic categories., Methods: Using data from three waves of the Netherlands Mental Health Survey and Incidence Study-2 (NEMESIS-2; n  = 6646), subjects with anxiety disorders (T 0; n  = 243) were divided into three mutually exclusive course trajectories according to their diagnostic status at 3-year (T 1 ) and 6-year (T 2 ) follow-up: remission group (no disorder at T 2 ), intermittent course group (no disorder at T 1 and disorder at T 2 ) and chronic course group (disorder at all measurements). Transition to residual symptoms or other psychopathology were studied. In addition, predictors of course trajectories were assessed., Results: During 6-year follow-up, 77.8% of subjects achieved remission, 14.0% followed an intermittent course and 8.2% a chronic course. Of those in remission, residual anxiety symptoms remained in 46.6%, while 7.9% developed another disorder between T 0 and T 2 . Compared with the remitting group, a chronic course was predicted by not living with a partner, multiple negative life events, neuroticism, lower mental functioning, severity of anxiety symptoms, use of mental health care and medication use., Limitations: The intermittent and chronic course groups were small, limiting statistical power. As a result, certain predictors may not have reached significance., Conclusions: In the general population at 6-year follow-up, 77.8% of subjects with anxiety disorders achieved remission. Because of transition to residual symptoms or another diagnostic category, only 52.4% of those subjects had a true favourable outcome.

Abstract: Predicting the onset and persistence of psychopathology and limited functioning might enable personalized care. Specific phobia (SP) might serve as a predictor, but this needs further evaluation. Participants of the Netherlands Mental Health Survey and Incidence Study-2 were divided into three groups: no-SP (n = 6094), history of SP (n = 204), and current SP (n = 348). Results showed that current SP was associated with a higher prevalence of other anxiety disorders, mood and substance use disorders, and lower levels of functioning. The 6-year onset of other anxiety disorders was associated with history and current SP. Current-SP was also associated with the onset of mood disorders. Neuroticism and childhood trauma only partly accounted for these associations. To conclude, SP was independently associated with presence and onset of other disorders and with limited functioning over time. The presence of SP may serve as an identifier of persons vulnerable to the development of other psychopathologies., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Few studies have investigated which patients with obsessive-compulsive disorder (OCD) do not recover through regular cognitive behavior therapy or pharmacotherapy and subsequently end up in intensive treatment like day treatment or inpatient treatment. Knowing the predictors of intensive treatment in these patients is significant because it could prevent intensive treatment. This study has identified predictors of intensive treatment in patients with OCD. Methods: Using 6-year longitudinal data of the Netherlands Obsessive Compulsive Disorder Association (NOCDA), potential predictors of intensive treatment were assessed in patients with OCD ( n = 419). Intensive treatment was assessed using the Treatment Inventory Costs in Patients with Psychiatric Disorders (TIC-P). Examined potential predictors were: sociodemographics, and clinical and psychosocial characteristics. Logistic Generalized Estimating Equations was used to estimate to what extent the various characteristics (at baseline, 2- and 4-year assessment) predicted intensive treatment in the following 2 years, averaged over the three assessment periods. Results: Being single, more severe comorbid depression, use of psychotropic medication, and a low quality of life predicted intensive treatment in the following 2 years. Conclusions: Therapists should be aware that patients with OCD who are single, who have more severe comorbid depression, who use psychotropic medication, and who have a low quality of life or a drop in quality of life are at risk for intensive treatment. Intensive treatment might be prevented by focusing regular treatment not only on OCD symptoms but also on comorbid depression and on quality of life. Intensive treatment might be improved by providing extra support in treatment or by adjusting treatment to impairments due to comorbid depressive symptoms or a low quality of life., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 du Mortier, Remmerswaal, Batelaan, Visser, Twisk, van Oppen and van Balkom.)

Objective: Despite the availability of mental health care, only a minority of depressed adolescents and young adults receive treatment. This study aimed to investigate facilitating factors and barriers in help-seeking behaviour of adolescents and young adults with depressive symptoms, using qualitative research methods., Methods: In-depth, semi-structured interviews with 32 participants with current or previous depressive symptoms aged 16 to 24 years using thematic content analysis., Findings: Our sample consisted mainly of adolescents who eventually found their way to professional help. Five main themes in help-seeking by adolescents and young adults were identified: (I) Individual functioning and well-being, (II) Health literacy, (III) Attitudinal aspects, (IV) Surroundings, and (V) Accessibility. Prompts to seek treatment were disease burden and poor academic performance. Health illiteracy negatively influenced treatment-seeking behaviour. Attitudinal aspects either hampered (shame, wanting to handle the problem oneself, negative attitudes towards treatment) or facilitated (positive attitudes towards treatment) help-seeking. Furthermore, adolescents' surroundings (school, family, and peers) appeared to play a critical role in the recognition of depressive symptoms and encouragement to seek help. Barriers regarding accessibility of mental health care were found, whereas direct and easy access to treatment greatly improved mental health care use., Conclusion: Facilitating factors can play a critical role in the help-seeking process of depressed adolescents and young adults, and may guide efforts to increase access to mental health care of this vulnerable age group. In particular, recognition and encouragement from school personnel and peers and easy access to care providers positively influenced help-seeking in our sample. Health illiteracy and attitudinal aspects appeared to be important barriers to seeking treatment and public/school campaigns aimed at reducing health illiteracy and stigma might be necessary to improve treatment-seeking and health care utilization in this age group., Competing Interests: The authors have declared that no competing interests exist.

Background: Data on episode duration of anxiety disorders are required for informing patients and for disease management, but such data from population studies are lacking., Methods: Three-year longitudinal data were used from the Netherlands Mental Health Survey and Incidence Study-2, a psychiatric epidemiological cohort study among the general adult population (N = 6646). Respondents with a new (first or recurrent) anxiety disorder were selected (n = 158). DSM-IV diagnoses were assessed with the Composite International Diagnostic Interview; the Life Chart Interview assessed episode duration and recovery rates., Results: Among those with anxiety disorder, median episode duration was 7.5 months and mean duration was 15.2 months. 38.8% had not recovered at 12 months and 30.1% not at 36 months. Longer duration was associated with older age, not having a paid job, higher neuroticism, more physical disorders, and worse physical functioning., Conclusions: Also, in the general population, anxiety disorder has a rather chronic course. After 12 months the cumulative recovery rate flattened. To prevent and manage chronicity, timely treatment, and chronic disease management are required. The risk indicators found may help to identify individuals with an anxiety disorder at risk for chronicity., (© 2020 Wiley Periodicals LLC.)

Background: Existing studies have yet to investigate the perspectives of patients and professionals concerning relapse prevention programs for patients with remitted anxiety or depressive disorders in primary care. User opinions should be considered when optimizing the use and implementation of interventions., Objective: This study aimed to evaluate the GET READY relapse prevention programs for patients with remitted anxiety or depressive disorders in general practice., Methods: Semistructured interviews (N=26) and focus group interviews (N=2) with patients and mental health professionals (MHPs) in the Netherlands were performed. Patients with remitted anxiety or depressive disorders and their MHPs who participated in the GET READY study were interviewed individually. Findings from the interviews were tested in focus group interviews with patients and MHPs. Data were analyzed using thematic analysis., Results: Participants were positive about the program because it created awareness of relapse risks. Lack of motivation, lack of recognizability, lack of support from the MHP, and symptom severity (too low or too high) appeared to be limiting factors in the use of the program. MHPs play a crucial role in motivating and supporting patients in relapse prevention. The perspectives of patients and MHPs were largely in accordance, although they had different perspectives concerning responsibilities for taking initiative., Conclusions: The implementation of the GET READY program was challenging. Guidance from MHPs should be offered for relapse prevention programs based on eHealth. Both MHPs and patients should align their expectations concerning responsibilities in advance to ensure optimal usage. Usage of blended relapse prevention programs may be further enhanced by diagnosis-specific programs and easily accessible support from MHPs., International Registered Report Identifier (irrid): RR2-10.1186/s12888-019-2034-6., (©Esther Krijnen-de Bruin, Jasmijn A Geerlings, Anna DT Muntingh, Willemijn D Scholten, Otto R Maarsingh, Annemieke van Straten, Neeltje M Batelaan, Berno van Meijel. Originally published in JMIR Formative Research (http://formative.jmir.org), 16.02.2021.)

Vulnerability markers for onset of anxiety disorders are scarce. In depression, patients at risk tend to respond with a negative mood to 'acute tryptophan depletion' (ATD), while healthy volunteers and current patients do not. The serotonergic system thus provides indications for vulnerability for depression. It is unknown whether ATD reveals vulnerability in anxiety too. This study systematically reviews the effects of ATD on anxiety and assesses whether challenging anxiety modifies the response. PubMed, Embase and PsychInfo were systematically searched up to April 2019 for studies in which (1) healthy volunteers or patients with a (remitted) anxiety disorder underwent ATD and (2) levels of anxiety were reported. In total, 21 studies were included. Studies conducted in healthy volunteers (n = 13), and patients with a remitted (n = 6) or current (panic, social or generalised) anxiety disorder (n = 4). Studies were mostly of poor quality and heterogeneous regarding population, challenge test used and outcome measures. ATD did not consistently affect anxiety in any of the groups. Moreover, a challenge test after ATD (n = 17 studies) did not consistently provoke anxiety in healthy volunteers or remitted patients. A 35% CO 2 challenge did consistently increase anxiety in patients with a current panic disorder (PD). To conclude, this systematic review found no clear indications that ATD provokes anxiety in those at risk for anxiety disorders. Hence, unlike in depression, ATD does not indicate vulnerability to develop an anxiety disorder. Because included studies were heterogeneous and mostly of poor quality, there is an urgent need for high quality research in homogeneous samples.

Objective: Patients with obsessive compulsive disorder (OCD) have high disease burden. It is important to restore quality of life (QoL) in treatment, so that patients become able to live a fulfilling life. Little is known about the longitudinal course of QoL in patients with OCD, its association with remission from OCD, and about factors that contribute to an unfavourable course of QoL in remitting patients., Methods: Study on the 4-year course of QoL of patients with chronic (n = 144), intermittent (n = 22), and remitting OCD (n = 73) using longitudinal data of the Netherlands Obsessive Compulsive Disorder Association (NOCDA; complete data: n = 239; imputed data n = 382). The EuroQol five-dimensional questionnaire (EQ-5D) utility score was used to assess QoL. In patients with remitting OCD, we examined patient characteristics that contributed to an unfavourable course of QoL, including sociodemographics, OCD characteristics, psychiatric comorbidity, and personality traits., Results: Course of QoL was associated with course of OCD. QoL improved in those who remitted from OCD; however, even in these patients, QoL remained significantly below the population norms. The correlation between QoL and severity of OCD was only moderate: r = - 0.40 indicating that other factors besides OCD severity contribute to QoL. In remitters, more severe anxiety and depression symptoms were related to a lower QoL. Results were similar in complete and imputed data sets., Conclusions: Remission from OCD is associated with improvement of QoL, but comorbid anxiety and depression symptoms hamper the improvement of QoL. QoL could be improved by reducing OCD symptoms in patients with OCD and by treating comorbid anxiety and depression symptoms in remitting patients.

Objective: Clinical characteristics appear limited in their ability to predict course of anxiety disorders, therefore we explored the predictive value of biological parameters on course of anxiety disorders., Methods: 907 persons with an anxiety (panic, social phobia, generalised anxiety) disorder with a baseline and two-year follow-up measure were selected from the Netherlands Study of Depression and Anxiety (NESDA). Previously, three course trajectories were distinguished which vary in terms of symptom severity and chronicity. Baseline clinical parameters like anxiety severity, anxiety duration, and disability were limited in their ability to predict the two-year course. This study explored whether metabolic syndrome, hypothalamic-pituitary-adrenal-axis functioning, inflammation markers, and neuroplasticity were indicators of two-year course and whether these parameters improved the model containing the most predictive clinical parameters only., Results: Baseline diastolic blood pressure of persons with chronic moderate symptoms was significantly higher than of persons with non-chronic mild symptoms (odds ratio [OR] = 1.18, 95% confidence interval [CI95%] 1.01 to 1.38). Baseline high-density lipid cholesterol of persons with severe chronic symptoms was significantly lower than of persons with non-chronic mild symptoms (OR = 0.77, CI95% 0.62 to 0.96). The predictive ability of both parameters was however low with concordance statistics of 0.55 and 0.57 respectively. Addition of biological parameters did not improve the predictive ability of the model containing the clinical parameters., Conclusions: In addition to clinical characteristics, biological parameters did not improve the predictive ability of the model for course trajectory of anxiety disorders. Prediction of course trajectory in anxiety disorders remains difficult and warrants further research., Competing Interests: Declaration of Competing Interest Declarations of interest: BP has received (non-related) research funding from Jansen Research and Boehringer Ingelheim. The other authors have nothing to declare., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Major depressive disorder (MDD) represents a leading cause of disability. This study examines the course of disability in patients with chronic, recurrent and remitting MDD compared to healthy controls and identifies predictors of disability in remitting MDD., Methods: We included 914 participants from the Netherlands Study of Depression and Anxiety (NESDA). DSM-IV MDD and WHO DAS II disability were assessed at baseline and at 2, 4 and 6 years. Six-year total and domain-specific disability were analysed and compared in participants with chronic (n = 57), recurrent (n = 120), remitting (n = 127) MDD and in healthy controls (n = 430). Predictors of residual disability were identified using linear regression analysis., Results: At baseline, most disability was found in chronic MDD, followed by recurrent MDD, remitting MDD and healthy controls. Across diagnostic groups, most disability was found in household activities, interpersonal functioning, participation in society and cognition. A chronic course was associated with chronic disability. Symptom remission was associated with a decrease in disability, but some disability remained. In remitting MDD, higher residual disability was predicted by older age, more severe avoidance symptoms, higher disability at baseline and late symptom remission. Severity of residual disability correlated with the severity of residual depressive symptoms., Conclusions: Symptomatic remission is a prerequisite for improvements in disability. However, disability persists despite symptom remission. Therefore, treatment of MDD should include an explicit focus on disability, especially on the more complex domains. To this end, treatments should promote behavioural activation and address subthreshold depressive symptoms in patients with remitted MDD.

Importance: Cognitive behavioral therapy is recommended for anxiety-related disorders, but evidence for its long-term outcome is limited., Objective: This systematic review and meta-analysis aimed to assess the long-term outcomes after cognitive behavioral therapy (compared with care as usual, relaxation, psychoeducation, pill placebo, supportive therapy, or waiting list) for anxiety disorders, posttraumatic stress disorder (PTSD), and obsessive-compulsive disorder (OCD)., Data Sources: English-language publications were identified from PubMed, PsycINFO, Embase, Cochrane, OpenGrey (1980 to January 2019), and recent reviews. The search strategy included a combination of terms associated with anxiety disorders (eg, panic or phobi*) and study design (eg, clinical trial or randomized controlled trial)., Study Selection: Randomized clinical trials on posttreatment and at least 1-month follow-up effects of cognitive behavioral therapy compared with control conditions among adults with generalized anxiety disorder, panic disorder with or without agoraphobia, social anxiety disorder, specific phobia, PTSD, or OCD., Data Extraction and Synthesis: Researchers independently screened records, extracted statistics, and assessed study quality. Data were pooled using a random-effects model., Main Outcomes and Measures: Hedges g was calculated for anxiety symptoms immediately after treatment and at 1 to 6 months, 6 to 12 months, and 12 months or more after treatment completion., Results: Of 69 randomized clinical trials (4118 outpatients) that were mainly of low quality, cognitive behavioral therapy compared with control conditions was associated with improved outcomes after treatment completion and at 1 to 6 months and at 6 to 12 months of follow-up for a generalized anxiety disorder (Hedges g, 0.07-0.40), panic disorder with or without agoraphobia (Hedges g, 0.22-0.35), social anxiety disorder (Hedges g, 0.34-0.60), specific phobia (Hedges g, 0.49-0.72), PTSD (Hedges g, 0.59-0.72), and OCD (Hedges g, 0.70-0.85). At a follow-up of 12 months or more, these associations were still significant for generalized anxiety disorder (Hedges g, 0.22; number of studies [k] = 10), social anxiety disorder (Hedges g, 0.42; k = 3), and PTSD (Hedges g, 0.84; k = 5), but not for panic disorder with or without agoraphobia (k = 5) and could not be calculated for specific phobia (k = 1) and OCD (k = 0). Relapse rates after 3 to 12 months were 0% to 14% but were reported in only 6 randomized clinical trials (predominantly for panic disorder with or without agoraphobia)., Conclusions and Relevance: The findings of this meta-analysis suggest that cognitive behavioral therapy for anxiety-related disorders is associated with improved outcomes compared with control conditions until 12 months after treatment completion. At a follow-up of 12 months or more, effects were small to medium for generalized anxiety disorder and social anxiety disorder, large for PTSD, and not significant or not available for other disorders. High-quality randomized clinical trials with 12 months or more of follow-up and reported relapse rates are needed.

Background: Obsessive-compulsive disorder (OCD) has a lifetime prevalence of 2-3% and is a leading cause of global disability. Brain circuit abnormalities in individuals with OCD have been identified, but important knowledge gaps remain. The goal of the new global initiative described in this paper is to identify robust and reproducible brain signatures of measurable behaviors and clinical symptoms that are common in individuals with OCD. A global approach was chosen to accelerate discovery, to increase rigor and transparency, and to ensure generalizability of results., Methods: We will study 250 medication-free adults with OCD, 100 unaffected adult siblings of individuals with OCD, and 250 healthy control subjects at five expert research sites across five countries (Brazil, India, Netherlands, South Africa, and the U.S.). All participants will receive clinical evaluation, neurocognitive assessment, and magnetic resonance imaging (MRI). The imaging will examine multiple brain circuits hypothesized to underlie OCD behaviors, focusing on morphometry (T1-weighted MRI), structural connectivity (Diffusion Tensor Imaging), and functional connectivity (resting-state fMRI). In addition to analyzing each imaging modality separately, we will also use multi-modal fusion with machine learning statistical methods in an attempt to derive imaging signatures that distinguish individuals with OCD from unaffected siblings and healthy controls (Aim #1). Then we will examine how these imaging signatures link to behavioral performance on neurocognitive tasks that probe these same circuits as well as to clinical profiles (Aim #2). Finally, we will explore how specific environmental features (childhood trauma, socioeconomic status, and religiosity) moderate these brain-behavior associations., Discussion: Using harmonized methods for data collection and analysis, we will conduct the largest neurocognitive and multimodal-imaging study in medication-free subjects with OCD to date. By recruiting a large, ethno-culturally diverse sample, we will test whether there are robust biosignatures of core OCD features that transcend countries and cultures. If so, future studies can use these brain signatures to reveal trans-diagnostic disease dimensions, chart when these signatures arise during development, and identify treatments that target these circuit abnormalities directly. The long-term goal of this research is to change not only how we conceptualize OCD but also how we diagnose and treat it.

Background: Clinical staging is a paradigm in which stages of disease progression are identified; these, in turn, have prognostic value. A staging model that enables the prediction of long-term course in anxiety disorders is currently unavailable but much needed as course trajectories are highly heterogenic. This study therefore tailored a heuristic staging model to anxiety disorders and assessed its validity., Methods: A clinical staging model was tailored to anxiety disorders, distinguishing nine stages of disease progression varying from subclinical stages (0, 1A, 1B) to clinical stages (2A-4B). At-risk subjects and subjects with anxiety disorders ( n  = 2352) from the longitudinal Netherlands Study of Depression and Anxiety were assigned to these nine stages. The model's validity was assessed by comparing baseline (construct validity) and 2-year, 4-year and 6-year follow-up (predictive validity) differences in anxiety severity measures across stages. Differences in depression severity and disability were assessed as secondary outcome measures., Results: Results showed that the anxiety disorder staging model has construct and predictive validity. At baseline, differences in anxiety severity, social avoidance behaviors, agoraphobic avoidance behaviors, worrying, depressive symptoms and levels of disability existed across all stages (all p -values < 0.001). Over time, these differences between stages remained present until the 6-year follow-up. Differences across stages followed a linear trend in all analyses: higher stages were characterized by the worst outcomes. Regarding the stages, subjects with psychiatric comorbidity (stages 2B, 3B, 4B) showed a deteriorated course compared with those without comorbidity (stages 2A, 3A, 4A)., Conclusion: A clinical staging tool would be useful in clinical practice to predict disease course in anxiety disorders.

Background: Depressive and anxiety disorders have shown to be associated to premature or advanced biological aging and consequently to adversely impact somatic health. Treatments with antidepressant medication or running therapy are both found to be effective for many but not all patients with mood and anxiety disorders. These interventions may, however, work through different pathophysiological mechanisms and could differ in their impact on biological aging and somatic health. This study protocol describes the design of an unique intervention study that examines whether both treatments are similarly effective in reducing or reversing biological aging (primary outcome), psychiatric status, metabolic stress and neurobiological indicators (secondary outcomes)., Methods: The MOod Treatment with Antidepressants or Running (MOTAR) study will recruit a total of 160 patients with a current major depressive and/or anxiety disorder in a mental health care setting. Patients will receive a 16-week treatment with either antidepressant medication or running therapy (3 times/week). Patients will undergo the treatment of their preference and a subsample will be randomized (1:1) to overcome preference bias. An additional no-disease-no-treatment group of 60 healthy controls without lifetime psychopathology, will be included as comparison group for primary and secondary outcomes at baseline. Assessments are done at week 0 for patients and controls, and at week 16 and week 52 for patients only, including written questionnaires, a psychiatric and medical examination, blood, urine and saliva collection and a cycle ergometer test, to gather information about biological aging (telomere length and telomerase activity), mental health (depression and anxiety disorder characteristics), general fitness, metabolic stress-related biomarkers (inflammation, metabolic syndrome, cortisol) and genetic determinants. In addition, neurobiological alterations in brain processes will be assessed using structural and functional Magnetic Resonance Imaging (MRI) in a subsample of at least 25 patients per treatment arm and in all controls., Discussion: This intervention study aims to provide a better understanding of the impact of antidepressant medication and running therapy on biological aging, metabolic stress and neurobiological indicators in patients with depressive and anxiety disorders in order to guide a more personalized medicine treatment., Trial Registration: Trialregister.nl Number of identification: NTR3460, May 2012.

Anxiety Disorders often show a chronic course, even when treated with one of the various effective treatments available. Lack of treatment effect could be due to Treatment Resistance (TR). Consensus on a definition for TR Anxiety Disorders (TR-AD) is highly needed as currently many different operationalizations are in use. Therefore, generalizability in current TR-AD research is suboptimal, hampering improvement of clinical care. The objective of this review is to evaluate the currently used definitions of TR-AD by performing a systematic review of available literature. Out of a total of n = 13 042, 62 studies that operationalized TR-AD were included. The current review confirms a lack of consensus on TR-AD criteria. In 62.9% of the definitions, TR was deemed present after the first treatment failure. Most studies (93.0%) required pharmacological treatment failures, whereas few (29.0%) required psychological treatment failures. However, criteria for what constitutes "treatment failure" were not provided in the majority of studies (58.1%). Definitions for minimal treatment duration ranged from at least 4 weeks to at least 6 months. Almost half of the TR-AD definitions (46.8%) required elevated anxiety severity levels in TR-AD. After synthesis of the results, the consensus definition considers TR-AD present after both at least one first-line pharmacological and one psychological treatment failure, provided for an adequate duration (at least 8 weeks) with anxiety severity remaining above a specified threshold. This definition could contribute to improving course prediction and identifying more targeted treatment options for the highly burdened subgroup of TR-AD patients., (© 2019 The Authors. Depression and Anxiety Published by Wiley Periodicals, Inc.)

Background: Anxiety and depressive disorders are increasingly being viewed as chronic conditions with fluctuating symptom levels. Relapse prevention programmes are needed to increase self-management and prevent relapse. Fine-tuning relapse prevention programmes to the needs of patients may increase uptake and effectiveness., Materials and Methods: A discrete choice experiment (DCE) was conducted amongst patients with a partially or fully remitted anxiety or depressive disorder. Patients were presented 20 choice tasks with two hypothetical treatment scenarios for relapse prevention, plus a "no treatment" option. Each treatment scenario was based on seven attributes of a hypothetical but realistic relapse prevention programme. Attributes considered professional contact frequency, treatment type, delivery mode, programme flexibility, a personal relapse prevention plan, time investment and effectiveness. Choice models were estimated to analyse the data., Results: A total of 109 patients with a partially or fully remitted anxiety or depressive disorder completed the DCE. Attributes with the strongest impact on choice were high effectiveness, regular contact with a professional, low time investment and the inclusion of a personal prevention plan. A high heterogeneity in preferences was observed, related to both clinical and demographic characteristics: for example, a higher number of previous treatment episodes was related to a preference for a higher frequency of contact with a professional, while younger age was related to a stronger preference for high effectiveness., Conclusions: This study using a DCE provides insights into preferences for a relapse prevention programme for anxiety and depressive disorders that can be used to guide the development of such a programme., Competing Interests: The authors have declared that no competing interests exist.

Background: This study examined the prevalence, course and risk indicators of subthreshold anxiety disorder to determine the necessity and possible risk indicators for interventions., Methods: Data were derived from the 'Netherlands Mental Health Survey and Incidence Study-2' (NEMESIS-2), a psychiatric epidemiological cohort study among the general population (n = 4528). This study assessed prevalence, characteristics, and three-year course of subthreshold anxiety disorder (n = 521) in adults, and compared them to a no anxiety group (n = 3832) and an anxiety disorder group (n = 175). Risk indicators for persistent and progressive subthreshold anxiety disorder were also explored, including socio-demographics, vulnerability factors, psychopathology, physical health and functioning., Results: The three-year prevalence of subthreshold anxiety disorder was 11.4%. At three-year follow-up, 57.3% had improved, 29.0% had persistent subthreshold anxiety disorder and 13.8% had progressed to a full-blown anxiety disorder. Prevalence, characteristics and course of subthreshold anxiety disorder were in between both comparison groups. Risk indicators for persistent course partly overlapped with those for progressive course and included vulnerability and psychopathological factors, and diminished functioning., Limitations: Course analysis were restricted to the development of anxiety disorders, other mental disorders were not assessed. Moreover, due to the naturalistic design of the study the impact of treatment on course cannot be assessed., Conclusions: Subthreshold anxiety disorder is relatively prevalent and at three-year follow-up a substantial part of respondents experienced persistent symptoms or had progressed into an anxiety disorder. Risk indicators like reduced functioning may help to identify these persons for (preventative) treatment and hence reduce functional limitations and disease burden., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Anxiety sensitivity is associated with the onset of panic attacks, anxiety, and other common mental disorders. Anxiety sensitivity is usually seen as a relative stable trait. However, previous studies were inconclusive regarding the longitudinal stability of anxiety sensitivity and differed in study designs and outcomes. The current study examines the stability of anxiety sensitivity over time and its longitudinal associations with severity of anxiety symptoms. Participants from the Netherlands Study of Depression and Anxiety with and without an anxiety, depressive, or comorbid anxiety-depressive disorder diagnosis were included (N = 2052). Stability in anxiety sensitivity over two year follow-up and the longitudinal association between the change in anxiety sensitivity and change in severity of anxiety symptoms were tested. Results indicated that two-year stability of anxiety sensitivity was high (r = 0.72), yet this test-retest estimate leaves room for changes in anxiety sensitivity in some individuals as well. Change in anxiety sensitivity was positively associated with change in severity of anxiety symptoms (B = 0.64 in univariable analysis and B = 0.52 in multivariable analysis). The longitudinal association of anxiety sensitivity with severity of anxiety symptoms indicates that targeting anxiety sensitivity may be of additional benefit in clinical practice.

Because the risk of relapse is high in anxiety disorders, it is important to bear in mind long-term prospects when making treatment decisions. This means that patients may need 'booster' treatment or continuous antidepressant medication to achieve long-term positive outcomes. Preparing a patient for a possible relapse in the end phase of a successful treatment, especially when there is a desire to discontinue the use of antidepressants, or timely intervention in case of an actual relapse episode is crucial to prevent recurrence of the anxiety disorder.

Background: Phobic anxiety disorders are among the most prevalent psychiatric disorders and are burdensome in terms of loss of quality of life and work productivity. Evidence-based treatments are relatively successful in the majority of patients, especially exposure therapy. However, a substantial subset of patients fails to achieve or stay in remission. Preclinical and genetic research have yielded evidence that the cannabinoid system is involved in the extinction of fear, presumed to underlie the beneficial effects of exposure therapy in phobic disorders. A cannabinoid constituent that may enhance endocannabinoid signaling is cannabidiol (CBD), a non-psychoactive component of cannabis. Hence, the addition of CBD to exposure therapy is expected to strengthen effects of treatment. To determine the added benefit of CBD on exposure therapy, we conduct a randomized controlled trial, in which patients in whom previous treatment as usual has not yielded sufficient response receive either CBD or placebo preceding 8 exposure sessions in a double-blind fashion. A subsidiary aim is to explore which (combination of) clinical, behavioral and genetic profiles of patients are related to treatment response., Methods/design: This is an 8-week multicenter, randomized, double-blind, placebo-controlled trial. Seventy-two patients with social phobia or panic disorder with agoraphobia with incomplete response to earlier treatment will be included from outpatient clinics in the Netherlands. Patients are randomized to augmentation of exposure therapy with 300 mg CBD or placebo. The study medication is administered orally, 2 h preceding each of the eight 90 min exposure sessions. Measurements will take place at baseline, first administration of medication, every session, mid-treatment, last administration of medication, post-treatment and at 3 and 6 months' follow-up. The primary outcome measure is the score on the Fear Questionnaire (FQ). In addition, determinants of the expected treatment enhancing effect of CBD will be explored., Discussion: This is the first trial to investigate whether the addition of CBD to exposure therapy is effective in reducing phobic symptoms in treatment refractory patients with social phobia or panic disorder with agoraphobia., Trial Registration: Netherlands Trial Register NTR5100 . Registered 13 March 2015. Protocol version: issue date 17 Jan 2018, protocol amendment number 7.