The definition of treatment resistance in anxiety disorders: a Delphi method-based consensus guideline.

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.

Predicting the naturalistic course in anxiety disorders using clinical and biological markers: a machine learning approach.

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.

A clinical staging approach to improving diagnostics in anxiety disorders: Is it the way to go?

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.

Aligning the many definitions of treatment resistance in anxiety disorders: A systematic review.

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.

Impact of Anxiety and/or Depressive Disorders and Chronic Somatic Diseases on disability and work impairment.

OBJECTIVE: Anxiety and/or Depressive Disorders (ADDs) and Chronic Somatic Diseases (CSDs) are associated with substantial levels of health-related disability and work impairment. However, it is unclear whether comorbid ADDs and CSDs additively affect functional outcomes. This paper examines the impact of ADDs, CSDs, and their comorbidity on disability, work absenteeism and presenteeism. METHODS: Baseline data from the Netherlands Study of Depression and Anxiety (n=2371) were used. We assessed presence of current ADDs (using psychiatric interviews, CIDI) and presence of self-reported CSDs. Outcome measures were disability scores (WHO-DAS II questionnaire, overall and domain-specific), work absenteeism (≤2weeks and >2weeks; TiC-P) and presenteeism (reduced and impaired work performance; TiC-P). We conducted multivariate regression analyses adjusted for socio-demographics. RESULTS: Both ADDs and CSDs significantly and independently impact total disability, but the impact was substantially larger for ADDs (main effect unstandardized ß=20.1, p<.001) than for CSDs (main effect unstandardized ß=3.88, p<.001). There was a positive interaction between ADDs and CSDs on disability (unstandardized ß interaction=4.06, p=.004). Although CSDs also induce absenteeism (OR for extended absenteeism=1.42, p=.015) and presenteeism (OR for impaired work performance=1.42, p=.013), associations with ADDs were stronger (OR for extended absenteeism=6.64, p<.001; OR for impaired work performance=7.51, p<.001). CONCLUSION: Both CSDs and ADDs cause substantial disability, work absenteeism and presenteeism, but the impact of ADDs far exceeds that of CSDs. CSDs and ADDs interact synergistically on disability, thereby bolstering the current view that patients with physical mental comorbidity (PM-comorbidity) form a severe subgroup with an unfavourable prognosis.

Feasibility and outcome of the implementation of a screening program for panic disorder in noncardiac chest pain patients in cardiac emergency department routine care.

OBJECTIVE: This study assesses the feasibility and outcome of the implementation of a screening program for classifying panic disorder (PD) in patients presenting with noncardiac chest pain (NCCP(1)), when integrated in routine cardiac emergency department (CED(2)) care. METHODS: Barrier analyses were made during the pilot phase and implementation period. NCCP patients aged 18-70 years presenting at the CED (n=252) were eligible for screening with the Hospital Anxiety and Depression Scale (HADS). Those scoring above cutoff on the HADS were referred to the psychiatric department and received the Composite International Diagnostic Interview. RESULTS: Screening was initiated in 60 patients (23.8%), of whom nine refused participation. Staff adherence remained low despite implementing several improvements in the screening procedure. In total, 39 patients completed the program; 8 were diagnosed with a psychiatric disorder, including 2 patients with PD. CONCLUSION: Feasibility of implementation of this screening program for PD in NCCP patients in routine CED care was limited because offering screening frequently conflicted with provision of acute care and because patients showed relatively high refusal rates. Contrasting our assumption, various other psychiatric disorders besides PD were classified.