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The definition of treatment resistance in anxiety disorders: a Delphi method‐based consensus guideline
Abstract
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.
... Anxiety disordersconstituting the most frequent mental disorders with a 12-month prevalence of 10-14% [1][2][3] confer a considerable individual and socioeconomic burden [4]. This is partly due to treatment resistance to first-line pharmacological or cognitive behavioral therapy (CBT) in 20-50% of patients [5][6][7][8] contributing to a substantial chronicity, with anxiety disorders ranking 6th among all disorders regarding the years lived with disability (YLDs) worldwide [9] (for review see [10]). ...
Epigenetic mechanisms such as DNA methylation are hypothesized to play a pivotal role in the pathogenesis of anxiety disorders and to predict as well as relate to treatment response. An epigenome-wide association study (EWAS) (Illumina MethylationEPIC BeadChip) was performed at baseline (BL), post-treatment (POST) and 6-month follow-up (FU) in the so far largest longitudinal sample of patients with anxiety disorders (N = 415) treated with exposure-based cognitive behavioral therapy (CBT), and in 315 healthy controls. Independent of comorbidity with depression, anxiety disorders were significantly (p ≤ 6.409E–08) associated with altered DNA methylation at 148 CpGs partly mapping to genes previously implicated in processes related to anxiety, brain disorders, learning or plasticity (e.g., GABBR2, GABRD, GAST, IL12RB2, LINC00293, LOC101928626, MFGE8, NOTCH4, PTPRN2, RIMBP2, SPTBN1) or in a recent cross-anxiety disorders EWAS (TAOK1) after pre-processing and quality control (N = 378 vs. N = 295). Furthermore, BL DNA methylation at seven and three CpGs, respectively, was suggestively (p < 1E–5) associated with treatment response at POST (ABCA7, ADRA2C, LTBR, RPSAP52, SH3RF3, SLC47A2, ZNF251) and FU (ADGRD1, PRSS58, USP47). Finally, suggestive evidence for dynamic epigenome-wide DNA methylation changes along with CBT response emerged at four CpGs from BL to FU (ADIPOR2, EIF3B, OCA2, TMCC1). The identification of epigenetic biomarkers may eventually aid in developing environment-based preventive strategies aimed at increasing resilience by providing deeper molecular insights into the mechanisms underlying anxiety disorders. Defining epigenetic signatures as predictors or key mechanisms in exposure-based interventions could pave the way for more targeted and personalized treatments for anxiety disorders.
... To avoid the theoretical difficulties of categorially excluding any response to a treatment, it has been recently suggested to prefer the more comprehensive term 'difficult-to-treat' depression [16,17]. In line with this recommendation, a Delphi methodbased consensus on the definition of treatment-resistant anxiety disorders [18] proposed the term "difficult-totreat" anxiety disorder due to its usefulness in the clinical context. ...
Background
Process-based therapy (PBT) is a new framework to intervention planning, based on the use of ecological momentary assessment (EMA) data and dynamic and idiographic network analyses. Support for its applicability has been reported from a single-case studies. Here, we examine the feasibility and effectiveness of PBT in a larger clinical sample. We have translated a training manual of PBT and modified for delivery of CBT in mental health service. The aim of this study is to test the relative efficacy of PBT compared to traditional CBT delivered in routine practice (r-CBT) for difficult-to-treat mood and anxiety disorders.
Methods
The study is a randomized controlled trial (RCT) of PBT vs r-CBT for difficult-to-treat unipolar depression and anxiety disorders. In total, 80 patients are recruited at an outpatient clinic and included in two intervention arms.
Primary outcome is emotional distress; secondary outcomes include psychological well-being and quality of life, adaptive behavior, psychological flexibility, and reflective functioning. Assessments of outcome variables are conducted before and after therapy and at 6 months follow-up. Weekly patient-rated outcomes are collected for every session to investigate process of change. Outcome assessors, blind to treatment allocation, will perform the observer-based symptom ratings, and adherence with manual will be monitored using self-report.
Discussion
The current study will be the first RCT of PBT in a health care setting. The planned moderator and mediator analyses will clarify the mechanisms of change in psychotherapy and the association between personalized assessment based on dynamic network analysis and treatment effect.
Trial registration
ClinicalTrials.gov NCT06517589. Registered 24 July 2024.
... However, given the considerable distress experienced, treatment-seeking persons frequently seek immediate relief, often leading to the prescription of fast-acting anxiolytic agents such as benzodiazepines (Roy-Byrne 2015), which can result in significant difficulties associated with long-term use (Soyka 2017). Furthermore, despite available intervention options backed by clinical guidelines (Bandelow et al. 2023), incidence cases have increased dramatically while existing treatments remain inconsistently effective (Shackman and Fox 2021) and a significant proportion of individuals with anxiety disorders display treatment resistance (Domschke et al. 2024), indicating the need for improved intervention options. Despite considerable research investment and ever-improving scientific methodologies, our mechanistic understanding of pathological anxiety and its translation from the lab to the clinic remains limited (Scull 2021;Cuthbert 2022). ...
Pathological anxiety is highly prevalent, impairing, and often chronic. Yet, despite considerable research, mechanistic understanding of anxiety and its translation to clinical practice remain limited. Here, we first highlight two foundational complications that contribute to this gap: a reliance on a phenomenology-driven definition of pathological anxiety in neurobiological mechanistic research, and a limited understanding of the chronicity of anxiety symptom expression. We then posit that anxiety symptoms may reflect aberrant expression of otherwise normative defensive responses. Accordingly, we propose that threat imminence, an organizing dimension for normative defensive responses observed across species, may be applied to organize and understand anxiety symptoms along a temporal dimension of expression. Empirical evidence linking distinct anxiety symptoms and the aberrant expression of imminence-dependent defensive responses is reviewed, alongside the neural mechanisms which may underpin these cognitive, physiological, and behavioral responses. Drawing from extensive translational and clinical research, we suggest that understanding anxiety symptoms through this neurobiologically-informed framework may begin to overcome the conceptual complications hindering advancement in mechanistic research and clinical interventions for pathological anxiety.
... Furthermore, in the early-onset group, but not in the later-onset group, logistic regression analysis showed that index mixed episode was predicted by a mixed first episode of illness. Numerous studies indicate that the course of bipolar illness is predominantly characterized by episodes of the same polarity as the first one [16,18,19]. Accordingly, our data suggest that the polarity of recurrences was likely to be predominantly mixed in this younger group of bipolar patients, often implying difficulties in therapeutical management. ...
Background: The present study aimed to examine clinical differences between subjects with early-onset (<21 years) and adult-onset (>30 years) bipolar I disorder, in particular, in relation to anxiety comorbidity.
Method: Subjects were selected from a cohort of 161 consecutive patients with bipolar disorder type I as diagnosed by the Structured Clinical Interview for DSM Disorder (SCID-I). Clinical characteristics and axis I comorbidity were compared between those whose illness first emerged before the age of 21 years (n=58) and those whose first episode occurred after the age of 30 years (n=27). Psychopathology was assessed using the 18-item version of the Brief Psychiatric Rating Scale (BPRS). The frequency of delusions, hallucinations, and formal thought disorders was evaluated with the SCID-I. Overall, social and occupational functioning was assessed by the Global Assessment of Functioning (GAF).
Results: Most subjects with early-onset bipolar disorder were males, had panic disorder and substance abuse comorbidity, longer duration of illness, exhibited mood-incongruent delusions, and presented with a mixed episode at onset more frequently than the later adult-onset subjects. Mixed mania at the first episode of illness and lifetime panic disorder comorbidity predicted mixed polarity at the first hospitalization episode in the early-onset subjects.
Conclusions: Overall, early age at onset seems to delineate a distinct bipolar I disorder subtype characterized by a greater likelihood of mixed episodes, lifetime panic disorder comorbidity, and schizophrenia-like delusions.
Objectives: Randomized controlled trials (RCTs) are the gold standard for evaluating medication efficacy. The absence of a universal definition of treatment response, based on the degree of symptom improvement measured by standardized rating scales in the field of attention-deficit/hyperactivity disorder (ADHD), makes it difficult to compare treatment outcomes across RCTs. Here, we aimed to assess to what extent and how "treatment response" is defined across RCTs of ADHD medications. Methods: We identified eligible RCTs via the MED-ADHD database (https://med-adhd.org/), which compiles RCTs evaluating the efficacy and safety of pharmacological treatments for children, adolescents, and adults with ADHD, based on a comprehensive search in multiple electronic databases, including PubMed, BIOSIS Previews, CINAHL, the Cochrane Central Registry of Controlled Trials, and EMBASE, up to 17 January 2025, alongside additional unpublished information gathered from manufacturers/study authors. Results: Out of 167 RCTs in MED-ADHD, 88 defined treatment response based on reductions in ADHD core symptom severity using rating scale scores. The most frequently used threshold was a ≥30% reduction in attention-deficit/hyperactivity disorder (ADHD-RS) scores, with other RCTs using ≥25%, ≥40%, or ≥50%. In addition, RCTs applied similar cutoff values to alternative scales, including Conner's Adult ADHD Rating Scale, SNAP-IV, Adult ADHD Investigator Rating Scale, and Wender-Reimherr Adult Attention Deficit Disorder Scale. However, 79 studies did not specify any response threshold. Conclusion: Our review underscores and quantitatively defines the inconsistency in the definition of treatment response across ADHD medication trials, highlighting the urgent need for the field to reach a consensus on the use of a standardized definition of "treatment response" for each rating scale, based on the percentage reduction in ADHD core symptom severity.
Anxiety disorders are among the most frequent psychiatric disorders. Although the vast majority of patients in Germany are treated on an outpatient basis, anxiety disorders also play an important role in day care and inpatient care. Among other aspects, this is against the background of comorbidities, treatment-resistant courses or complications such as suicidal ideation.
As part of an evaluation of the basic psychiatric documentation (BADO) data from 894 patients with anxiety disorders treated in a day care or inpatient setting in a German psychiatric community hospital were evaluated over a period of 7 years.
It was found that 89% of the patients had already been treated before admission and that 70% had been under medication prior to admission: patients with panic disorder made up the largest group of patients with 48%. On the date of admission 48% of patients had been treated with a selective serotonin reuptake inhibitor (SSRI) and 37% had received a benzodiazepine. Furthermore, 75% of the patients had psychiatric comorbidities. Somatic illnesses played an important role in 40% of the patients.
The present results underline that a significant proportion of patients with anxiety disorders also require inpatient or day care treatment. Most patients had been previously treated and had not responded to therapy in an outpatient setting. Possible consequences with respect to the optimization of outpatient treatment options and the need to maintain day care and inpatient resources for this patient group, are discussed.
Background
This is a new algorithm from the Psychopharmacology Algorithm Project at the Harvard South Shore Program, focused on generalized anxiety disorder (GAD) in older adults. Pertinent articles were identified and reviewed.
Results
Selective serotonin reuptake inhibitors (SSRIs) are considered to be first-line medications, with a preference for sertraline or escitalopram. If avoiding sexual side effects is a priority, buspirone is an option for the relatively healthy older adult. If response is inadequate, the second recommended trial is with a different SSRI or one of the serotonin-norepinephrine update inhibitors (SNRIs), venlafaxine or duloxetine. For a third medication trial, additional alternatives added to the previous options now include pregabalin/gabapentin, lavender oil, and agomelatine. If there is an unsatisfactory response to the third option chosen, quetiapine may be considered. We recommend caution with the following for acute treatment in this population: benzodiazepines and hydroxyzine. Other agents given low priority but having some supportive evidence were vilazodone, vortioxetine, mirtazapine, and cannabidiol. Acknowledging that the median age of onset of GAD is in early adulthood, many patients with GAD will have been started on benzodiazepines (or other medications that require caution in the elderly) for GAD at a younger age. These medications may be continued with regular observation to see if the potential harms are starting to exceed the benefits and a switch to other recommended agents may be justified.
As Faculty of the British Association for Psychopharmacology course on child and adolescent psychopharmacology, we present here what we deem are the most common pitfalls, and how to avoid them, in child and adolescent psychopharmacology. In this paper, we specifically addressed common pitfalls in the pharmacological treatment of attention-deficit/hyperactivity disorder, anxiety, bipolar disorder, depression, obsessive-compulsive disorder and related disorders, and tic disorder. Pitfalls in the treatment of other disorders are addressed in a separate paper (part II).
Treatment resistance in anxiety disorders represents a clinical challenge, contributes to the chronicity of the diseases as well as sequential comorbidities, and is associated with a significant individual and socioeconomic burden. This narrative review presents the operational definition of treatment resistance in anxiety disorders according to international consensus criteria (< 50% reduction in the Hamilton Anxiety Scale, HAM‑A, score or < 50% reduction in the Beck Anxiety Inventory, BAI, score or a clinical global impression-improvement, CGI‑I, score > 2). At least two unsuccessful guideline-based treatment attempts with pharmacological monotherapy or at least one unsuccessful treatment attempt with adequately delivered cognitive behavioral therapy are required. Pharmacotherapeutically, after excluding pseudo-resistance, switching the medication within one class or to another class and augmentation strategies with other antidepressants (mirtazapine, agomelatine), antipsychotics (quetiapine) or anticonvulsants (valproate) are recommended. Psychotherapeutically, third-wave therapies, psychodynamic therapy, systemic therapy and physical exercise can be considered for therapy resistance. In cases of no response to psychotherapy or pharmacotherapy, the respective other form of therapy or a combination of both should be offered. Compounds targeting the glutamatergic and endocannabinoid systems as well as neuropeptides are being tested as potential innovative pharmaceuticals for treatment-resistant anxiety disorders. There is an urgent need for further research to identify predictive markers and mechanisms as well as to develop innovative pharmacological and psychotherapeutic interventions for treatment-resistant anxiety disorders.
Treatment‐resistant depression (TRD) is common and associated with multiple serious public health implications. A consensus definition of TRD with demonstrated predictive utility in terms of clinical decision‐making and health outcomes does not currently exist. Instead, a plethora of definitions have been proposed, which vary significantly in their conceptual framework. The absence of a consensus definition hampers precise estimates of the prevalence of TRD, and also belies efforts to identify risk factors, prevention opportunities, and effective interventions. In addition, it results in heterogeneity in clinical practice decision‐making, adversely affecting quality of care. The US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have adopted the most used definition of TRD (i.e., inadequate response to a minimum of two antidepressants despite adequacy of the treatment trial and adherence to treatment). It is currently estimated that at least 30% of persons with depression meet this definition. A significant percentage of persons with TRD are actually pseudo‐resistant (e.g., due to inadequacy of treatment trials or non‐adherence to treatment). Although multiple sociodemographic, clinical, treatment and contextual factors are known to negatively moderate response in persons with depression, very few factors are regarded as predictive of non‐response across multiple modalities of treatment. Intravenous ketamine and intranasal esketamine (co‐administered with an antidepressant) are established as efficacious in the management of TRD. Some second‐generation antipsychotics (e.g., aripiprazole, brexpiprazole, cariprazine, quetiapine XR) are proven effective as adjunctive treatments to antidepressants in partial responders, but only the olanzapine‐fluoxetine combination has been studied in FDA‐defined TRD. Repetitive transcranial magnetic stimulation (TMS) is established as effective and FDA‐approved for individuals with TRD, with accelerated theta‐burst TMS also recently showing efficacy. Electroconvulsive therapy is regarded as an effective acute and maintenance intervention in TRD, with preliminary evidence suggesting non‐inferiority to acute intravenous ketamine. Evidence for extending antidepressant trial, medication switching and combining antidepressants is mixed. Manual‐based psychotherapies are not established as efficacious on their own in TRD, but offer significant symptomatic relief when added to conventional antidepressants. Digital therapeutics are under study and represent a potential future clinical vista in this population.
The Patient Health Questionnaire-9 (PHQ-9) and Generalized Anxiety Disorder-7 (GAD-7) are short self-report questionnaires used to screen and assess depression and anxiety severity in medical and community samples. However, little is known about their psychometric properties in individuals with anxiety and mood disorders (AMD) This study evaluated the psychometric properties of the PHQ-9 and GAD-7 in individuals with AMD. Individuals (n = 244, mean age 39.9 ± 12.3 years) with AMD completed the PHQ-9, GAD-7, as well as other measures of depression, anxiety, and a structured diagnostic interview. The PHQ-9 and GAD-7 demonstrated good internal consistency (Cronbach's alpha 0.87 and 0.84, respectively). The PHQ-9 and GAD-7 showed a weak correlation with clinician-rated scales HAM-D and HAM-A (r = 0.316, p < 0.01, r = 0.307, p < 0.01, respectively). For the PHQ-9, a cut score of ≥11 resulted in 72% sensitivity and 72% specificity at recognizing depression symptoms. For the GAD-7, a cut score ≥7 resulted in 73% sensitivity and 54% specificity at recognizing any anxiety disorders. The confirmatory factor analysis suggested a two-factor structure ("cognitive/affectional", "somatic") for both the PHQ-9 and GAD-7. In conclusion, the PHQ-9 and GAD-7 have adequate formal psychometric properties as severity measures for symptoms of anxiety and depression in individuals with AMD. The PHQ-9 performs well as a screener using a cut score of ≥11. However, the clinical utility of the GAD-7 as a diagnostic tool for recognition of anxiety disorders is limited.
The field of psychiatry is hampered by a lack of robust, reliable and valid biomarkers that can aid in objectively diagnosing patients and providing individualized treatment recommendations. Here we review and critically evaluate the evidence for the most promising biomarkers in the psychiatric neuroscience literature for autism spectrum disorder, schizophrenia, anxiety disorders and post‐traumatic stress disorder, major depression and bipolar disorder, and substance use disorders. Candidate biomarkers reviewed include various neuroimaging, genetic, molecular and peripheral assays, for the purposes of determining susceptibility or presence of illness, and predicting treatment response or safety. This review highlights a critical gap in the biomarker validation process. An enormous societal investment over the past 50 years has identified numerous candidate biomarkers. However, to date, the overwhelming majority of these measures have not been proven sufficiently reliable, valid and useful to be adopted clinically. It is time to consider whether strategic investments might break this impasse, focusing on a limited number of promising candidates to advance through a process of definitive testing for a specific indication. Some promising candidates for definitive testing include the N170 signal, an event‐related brain potential measured using electroencephalography, for subgroup identification within autism spectrum disorder; striatal resting‐state functional magnetic resonance imaging (fMRI) measures, such as the striatal connectivity index (SCI) and the functional striatal abnormalities (FSA) index, for prediction of treatment response in schizophrenia; error‐related negativity (ERN), an electrophysiological index, for prediction of first onset of generalized anxiety disorder, and resting‐state and structural brain connectomic measures for prediction of treatment response in social anxiety disorder. Alternate forms of classification may be useful for conceptualizing and testing potential biomarkers. Collaborative efforts allowing the inclusion of biosystems beyond genetics and neuroimaging are needed, and online remote acquisition of selected measures in a naturalistic setting using mobile health tools may significantly advance the field. Setting specific benchmarks for well‐defined target application, along with development of appropriate funding and partnership mechanisms, would also be crucial. Finally, it should never be forgotten that, for a biomarker to be actionable, it will need to be clinically predictive at the individual level and viable in clinical settings.
Anxiety disorders are increasingly prevalent, affect people’s ability to do things, and decrease quality of life. Due to lack of objective tests, they are underdiagnosed and sub-optimally treated, resulting in adverse life events and/or addictions. We endeavored to discover blood biomarkers for anxiety, using a four-step approach. First, we used a longitudinal within-subject design in individuals with psychiatric disorders to discover blood gene expression changes between self-reported low anxiety and high anxiety states. Second, we prioritized the list of candidate biomarkers with a Convergent Functional Genomics approach using other evidence in the field. Third, we validated our top biomarkers from discovery and prioritization in an independent cohort of psychiatric subjects with clinically severe anxiety. Fourth, we tested these candidate biomarkers for clinical utility, i.e. ability to predict anxiety severity state, and future clinical worsening (hospitalizations with anxiety as a contributory cause), in another independent cohort of psychiatric subjects. We showed increased accuracy of individual biomarkers with a personalized approach, by gender and diagnosis, particularly in women. The biomarkers with the best overall evidence were GAD1, NTRK3, ADRA2A, FZD10, GRK4, and SLC6A4. Finally, we identified which of our biomarkers are targets of existing drugs (such as a valproate, omega-3 fatty acids, fluoxetine, lithium, sertraline, benzodiazepines, and ketamine), and thus can be used to match patients to medications and measure response to treatment. We also used our biomarker gene expression signature to identify drugs that could be repurposed for treating anxiety, such as estradiol, pirenperone, loperamide, and disopyramide. Given the detrimental impact of untreated anxiety, the current lack of objective measures to guide treatment, and the addiction potential of existing benzodiazepines-based anxiety medications, there is a urgent need for more precise and personalized approaches like the one we developed.
Background
Over the last 20 years, compassion focused therapy (CFT) has gained popularity as an emerging ‘third wave’ intervention. Although previous reviews indicated its potential benefits, a systematic review and meta-analysis of CFT in those with mental health difficulties has yet to be conducted.
Methods
A systematic search of five databases was undertaken, focusing on randomised controlled trials and randomised pilot/feasibility studies of CFT only. No language restrictions were implemented. A narrative synthesis was conducted. Random effects meta-analyses were measured on levels of self-compassion, self-criticism/self-reassurance, fears of compassion and clinical symptomology.
Results
Fifteen studies from 2013 to 2022 were included. Findings suggested that CFT was effective in improving compassion-based outcomes and clinical symptomology from baseline to post-intervention and compared to waitlist control. A range of small to large effect sizes were reported for improvements in self-compassion (0.19–0.90), self-criticism (0.15–0.72), self-reassurance (0.43–0.81), fear of self-compassion (0.18), depression (0.24–0.25) and eating disorders (0.18–0.79). Meta-analyses favoured CFT in improving levels of self-compassion and self-reassurance than control groups.
Limitations
The methodological quality of many of the included studies (7/15) was rated as ‘unclear’ due to a lack of information. There was a distinct gender gap, with 76.1 % identifying as female participants.
Conclusions
This review was the first to examine the effectiveness of CFT in clinical populations. The results indicate that CFT has promising clinical implications, suggesting that the intervention increases compassion-based outcomes and reduces clinical symptomology in those with mental health difficulties. However, future research is required into the long-term effects of CFT.
Psychiatric disorders associated with psychological trauma, stress and anxiety are a highly prevalent and increasing cause of morbidity worldwide. Current therapeutic approaches, including medication, are effective in alleviating symptoms of anxiety disorders and posttraumatic stress disorder (PTSD), at least in some individuals, but have unwanted side-effects and do not resolve underlying pathophysiology. After a period of stagnation, there is renewed enthusiasm from public, academic and commercial parties in designing and developing drug treatments for these disorders. Here, we aim to provide a snapshot of the current state of this field that is written for neuropharmacologists, but also practicing clinicians and the interested lay-reader. After introducing currently available drug treatments, we summarize recent/ongoing clinical assessment of novel medicines for anxiety and PTSD, grouped according to primary neurochemical targets and their potential to produce acute and/or enduring therapeutic effects. The evaluation of putative treatments targeting monoamine (including psychedelics), GABA, glutamate, cannabinoid, cholinergic and neuropeptide systems, amongst others, are discussed. We emphasize the importance of designing and clinically assessing new medications based on a firm understanding of the underlying neurobiology stemming from the rapid advances being made in neuroscience. This includes harnessing neuroplasticity to bring about lasting beneficial changes in the brain rather than - as many current medications do - produce a transient attenuation of symptoms, as exemplified by combining psychotropic/cognitive enhancing drugs with psychotherapeutic approaches. We conclude by noting some of the other emerging trends in this promising new phase of drug development.
Anxiety disorders (generalized anxiety disorder, panic disorder/agoraphobia, social anxiety disorder, and others) are the most prevalent psychiatric disorders, and are associated with a high burden of illness. Anxiety disorders are often underrecognized and undertreated in primary care. Treatment is indicated when a patient shows marked distress or suffers from complications resulting from the disorder. The treatment recommendations given in this article are based on guidelines, meta-analyses, and systematic reviews of randomized controlled studies. Anxiety disorders should be treated with psychological therapy, pharmacotherapy, or a combination of both. Cognitive behavioral therapy can be regarded as the psychotherapy with the highest level of evidence. First-line drugs are the selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors. Benzodiazepines are not recommended for routine use. Other treatment options include pregabalin, tricyclic antidepressants, buspirone, moclobemide, and others. After remission, medications should be continued for 6 to 12 months. When developing a treatment plan, efficacy, adverse effects, interactions, costs, and the preference of the patient should be considered.
Background
The Patient Health Questionnaire—9 (PHQ-9) and the Generalized Anxiety Disorder Questionnaire– 7 (GAD-7) are short screening instruments used for detection of depression and anxiety symptoms in various settings, including general and mental health care as well as the general population. The aim of this study is to evaluate psychometric properties and factorial structure of the PHQ-9 and the GAD-7 in a sample of Lithuanian university students.
Methods
1368 students (mean age 22.5±4.8) completed the PHQ-9 and the GAD-7 questionnaires online; after the completion of the survey, students were asked to provide phone contact for an additional interview. Eligible students were approached later by trained interviewers and completed The Clinical Interview Schedule-Revised for assessment of depressive and anxiety disorders.
Results
Results showed that the PHQ-9 and the GAD-7 are reliable screening tools for depression and anxiety (Cronbach alpha 0.86 and 0.91, respectively). The one-factor structure of the PHQ-9 and the GAD-7 was confirmed by the Confirmatory Factor Analysis. A cut-off of ≥10 for the PHQ-9 resulted in 71% sensitivity and 66% specificity recognizing students with increased risk for mood or anxiety disorder. For the GAD-7, a cut-off ≥9 resulted in 73% sensitivity and 70% specificity recognizing students at risk. The PHQ-9 was sensitive but not specific in recognizing students with depressive disorders. The sensitivity and specificity of the GAD-7 in differentiating students with generalized anxiety disorders were low.
Conclusions
The PHQ-9 and the GAD-7 have sufficient formal psychometric properties, but their clinical utility as diagnostic tools for recognition of depressive and anxiety disorders in students is limited. Due to low specificity and high false positive rates, both scales are recommended only as an initial screening tool for recognition of subjects with increased risk of mental disorders, however positive cases should be later assessed using more comprehensive instruments.
Mental health problems often involve clusters of symptoms that include subjective (conscious) experiences as well as behavioral and/or physiological responses. Because the bodily responses are readily measured objectively, these have come to be emphasized when developing treatments and assessing their effectiveness. On the other hand, the subjective experience of the patient reported during a clinical interview is often viewed as a weak correlate of psychopathology. To the extent that subjective symptoms are related to the underlying problem, it is often assumed that they will be taken care of if the more objective behavioral and physiological symptoms are properly treated. Decades of research on anxiety disorders, however, show that behavioral and physiological symptoms do not correlate as strongly with subjective experiences as is typically assumed. Further, the treatments developed using more objective symptoms as a marker of psychopathology have mostly been disappointing in effectiveness. Given that “mental” disorders are named for, and defined by, their subjective mental qualities, it is perhaps not surprising, in retrospect, that treatments that have sidelined mental qualities have not been especially effective. These negative attitudes about subjective experience took root in psychiatry and allied fields decades ago when there were few avenues for scientifically studying subjective experience. Today, however, cognitive neuroscience research on consciousness is thriving, and offers a viable and novel scientific approach that could help achieve a deeper understanding of mental disorders and their treatment.
Background: The mental disorders included in the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019 were depressive disorders, anxiety disorders, bipolar disorder, schizophrenia, autism spectrum disorders, conduct disorder, attention-deficit hyperactivity disorder, eating disorders, idiopathic developmental intellectual disability, and a residual category of other mental disorders. We aimed to measure the global, regional, and national prevalence, disability-adjusted life-years (DALYS), years lived with disability (YLDs), and years of life lost (YLLs) for mental disorders from 1990 to 2019.
Methods: In this study, we assessed prevalence and burden estimates from GBD 2019 for 12 mental disorders, males and females, 23 age groups, 204 countries and territories, between 1990 and 2019. DALYs were estimated as the sum of YLDs and YLLs to premature mortality. We systematically reviewed PsycINFO, Embase, PubMed, and the Global Health Data Exchange to obtain data on prevalence, incidence, remission, duration, severity, and excess mortality for each mental disorder. These data informed a Bayesian meta-regression analysis to estimate prevalence by disorder, age, sex, year, and location. revalence was multiplied by corresponding disability weights to estimate YLDs. Cause-specific deaths were compiled from mortality surveillance databases. The Cause of Death Ensemble modelling strategy was used to estimate death rate by age, sex, year, and location. The death rates were multiplied by the years of life expected to be remaining at death based on a normative life expectancy to estimate YLLs. Deaths and YLLs could be calculated only for anorexia nervosa and bulimia nervosa, since these were the only mental disorders identified as underlying causes of death in GBD 2019.
Findings: Between 1990 and 2019, the global number of DALYs due to mental disorders increased from 80·8 million (95% uncertainty interval [UI] 59·5–105·9) to 125·3 million (93·0–163·2), and the proportion of global DALYs attributed to mental disorders increased from 3·1% (95% UI 2·4–3·9) to 4·9% (3·9–6·1). Age-standardised DALY rates remained largely consistent between 1990 (1581·2 DALYs [1170·9–2061·4] per 100 000 people) and 2019 (1566·2 DALYs [1160·1–2042·8] per 100 000 people). YLDs contributed to most of the mental disorder burden, with 125·3 million YLDs (95% UI 93·0–163·2; 14·6% [12·2–16·8] of global YLDs) in 2019 attributable to mental disorders. Eating disorders accounted for 17 361·5 YLLs (95% UI 15 518·5–21 459·8). Globally, the age-standardised DALY rate for mental disorders was 1426·5 (95% UI 1056·4–1869·5) per 100 000 population among males and 1703·3 (1261·5–2237·8) per 100 000 population among females. Age-standardised DALY rates were highest in Australasia, Tropical Latin America, and high-income North America.
Interpretation: GBD 2019 showed that mental disorders remained among the top ten leading causes of burden worldwide, with no evidence of global reduction in the burden since 1990. The estimated YLLs for mental disorders were extremely low and do not reflect premature mortality in individuals with mental disorders. Research to establish causal pathways between mental disorders and other fatal health outcomes is recommended so that this may be addressed within the GBD study. To reduce the burden of mental disorders, coordinated delivery of effective prevention and treatment programmes by governments and the global health community is imperative.
Approximately one-third of individuals in a major depressive episode will not achieve sustained remission despite multiple, well-delivered treatments. These patients experience prolonged suffering and disproportionately utilize mental and general health care resources. The recently proposed clinical heuristic of ‘difficult-to-treat depression’ (DTD) aims to broaden our understanding and focus attention on the identification, clinical management, treatment selection, and outcomes of such individuals. Clinical trial methodologies developed to detect short-term therapeutic effects in treatment-responsive populations may not be appropriate in DTD. This report reviews three essential challenges for clinical intervention research in DTD: (1) how to define and subtype this heterogeneous group of patients; (2) how, when, and by what methods to select, acquire, compile, and interpret clinically meaningful outcome metrics; and (3) how to choose among alternative clinical trial design options to promote causal inference and generalizability. The boundaries of DTD are uncertain, and an evidence-based taxonomy and reliable assessment tools are preconditions for clinical research and subtyping. Traditional outcome metrics in treatment-responsive depression may not apply to DTD, as they largely reflect the only short-term symptomatic change and do not incorporate durability of benefit, side effect burden, or sustained impact on quality of life or daily function. The trial methodology will also require modification as trials will likely be of longer duration to examine the sustained impact, raising complex issues regarding control group selection, blinding and its integrity, and concomitant treatments.
Criteria for treatment-resistant depression (TRD) and partially responsive depression (PRD) as subtypes of major depressive disorder (MDD) are not unequivocally defined. In the present document we used a Delphi-method-based consensus approach to define TRD and PRD and to serve as operational criteria for future clinical studies, especially if conducted for regulatory purposes. We reviewed the literature and brought together a group of international experts (including clinicians, academics, researchers, employees of pharmaceutical companies, regulatory bodies representatives, and one person with lived experience) to evaluate the state-of-the-art and main controversies regarding the current classification. We then provided recommendations on how to design clinical trials, and on how to guide research in unmet needs and knowledge gaps. This report will feed into one of the main objectives of the EUropean Patient-cEntric clinicAl tRial pLatforms, Innovative Medicines Initiative (EU-PEARL, IMI) MDD project, to design a protocol for platform trials of new medications for TRD/PRD.
Objective
Metacognitive therapy (MCT) and cognitive–behavior therapy (CBT) are effective treatments for generalized anxiety disorder. In this study, we followed-up patients who had previously participated in a randomized controlled trial of MCT compared against CBT.
Method
We collected 9-year follow-up data on 39 out of 60 original patients (i.e., 65% response rate).
Results
At 9 years, the recovery rates were 57% for MCT and 38% for CBT (completer analysis). Following MCT, 43% maintained their recovery status and a further 14% achieved recovery. Following CBT, the sustained recovery rate was 13%, while a further 25% achieved recovery. Patients in the MCT condition showed significantly more improvement with respect to symptoms of worry and anxiety. In the CBT group, 23.1% were re-diagnosed with generalized anxiety disorder (GAD) compared with 9.5% in the MCT group.
Conclusions
This follow-up study showed a continuation of gains in both treatments at long-term follow-up, but with outcomes continuing to favor MCT and strengthening its comparative superiority.
The clinical construct of “anxiety neurosis” was broad and poorly defined, so that the delineation of specific anxiety disorders in the DSM-III was an important advance. However, anxiety and related disorders are not only frequently comorbid, but each is also quite heterogeneous; thus diagnostic manuals provide only a first step towards formulating a management plan, and the development of additional decision support tools for the treatment of anxiety conditions is needed. This paper aims to describe systematically important domains that are relevant to the personalization of management of anxiety and related disorders in adults. For each domain, we summarize the available research evidence and review the relevant assessment instruments, paying special attention to their suitability for use in routine clinical practice. We emphasize areas where the available evidence allows the clinician to personalize the management of anxiety conditions, and we point out key unmet needs. Overall, the evidence suggests that we are becoming able to move from simply recommending that anxiety and related disorders be treated with selective serotonin reuptake inhibitors, cognitive-behavioral therapy, or their combination, to a more complex approach which emphasizes that the clinician has a broadening array of management modalities available, and that the treatment of anxiety and related disorders can already be personalized in a number of important respects.
Treatment resistance affects 20–60% of patients with psychiatric disorders; and is associated with increased healthcare burden and costs up to ten-fold higher relative to patients in general. Whilst there has been a recent increase in the proportion of psychiatric research focussing on treatment resistance (R2 = 0.71, p < 0.0001), in absolute terms this is less than 1% of the total output and grossly out of proportion to its prevalence and impact. Here, we provide an overview of treatment resistance, considering its conceptualisation, assessment, epidemiology, impact, and common neurobiological models. We also review new treatments in development and future directions. We identify 23 consensus guidelines on its definition, covering schizophrenia, major depressive disorder, bipolar affective disorder, and obsessive compulsive disorder (OCD). This shows three core components to its definition, but also identifies heterogeneity and lack of criteria for a number of disorders, including panic disorder, post-traumatic stress disorder, and substance dependence. We provide a reporting check-list to aid comparisons across studies. We consider the concept of pseudo-resistance, linked to poor adherence or other factors, and provide an algorithm for the clinical assessment of treatment resistance. We identify nine drugs and a number of non-pharmacological approaches being developed for treatment resistance across schizophrenia, major depressive disorder, bipolar affective disorder, and OCD. Key outstanding issues for treatment resistance include heterogeneity and absence of consensus criteria, poor understanding of neurobiology, under-investment, and lack of treatments. We make recommendations to address these issues, including harmonisation of definitions, and research into the mechanisms and novel interventions to enable targeted and personalised therapeutic approaches.
Anxiety disorders are prevalent and highly disabling mental disorders. In recent years, intensive efforts focused on the search for potential neuroimaging, genetic, and peripheral biomarkers in order to better understand the pathophysiology of these disorders, support their diagnosis, and characterize the treatment response. Of note, peripheral blood biomarkers, as surrogates for the central nervous system, represent a promising instrument to characterize psychiatric disorders, although their role has not been extensively applied to clinical practice. In this report, the state of the art on peripheral biomarkers of DSM-5 (Diagnostic and Statistical Manual of Mental Disorders, 5th edition) Anxiety Disorders is presented, in order to examine their role in the pathogenesis of these conditions and their potential application for diagnosis and treatment. Available data on the cerebrospinal fluid and blood-based biomarkers related to neurotransmitters, neuropeptides, the hypothalamic–pituitary–adrenal axis, neurotrophic factors, and the inflammation and immune system are reviewed. Despite the wide scientific literature and the promising results in the field, only a few of the proposed peripheral biomarkers have been defined as a specific diagnostic instrument or have been identified as a guide in the treatment response to DSM-5 Anxiety Disorders. Therefore, further investigations are needed to provide new biological insights into the pathogenesis of anxiety disorders, to help in their diagnosis, and to tailor a treatment.
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 develop an instrument to evaluate the credibility of anchor based minimal important differences (MIDs) for outcome measures reported by patients, and to assess the reliability of the instrument.
Design
Instrument development and reliability study.
Data sources
Initial criteria were developed for evaluating the credibility of anchor based MIDs based on a literature review (Medline, Embase, CINAHL, and PsycInfo databases) and the experience of the authors in the methodology for estimation of MIDs. Iterative discussions by the team and pilot testing with experts and potential users facilitated the development of the final instrument.
Participants
With the newly developed instrument, pairs of masters, doctoral, or postdoctoral students with a background in health research methodology independently evaluated the credibility of a sample of MID estimates.
Main outcome measures
Core credibility criteria applicable to all anchor types, additional criteria for transition rating anchors, and inter-rater reliability coefficients were determined.
Results
The credibility instrument has five core criteria: the anchor is rated by the patient; the anchor is interpretable and relevant to the patient; the MID estimate is precise; the correlation between the anchor and the outcome measure reported by the patient is satisfactory; and the authors select a threshold on the anchor that reflects a small but important difference. The additional criteria for transition rating anchors are: the time elapsed between baseline and follow-up measurement for estimation of the MID is optimal; and the correlations of the transition rating with the baseline, follow-up, and change score in the patient reported outcome measures are satisfactory. Inter-rater reliability coefficients (ĸ) for the core criteria and for one item from the additional criteria ranged from 0.70 to 0.94. Reporting issues prevented the evaluation of the reliability of the three other additional criteria for the transition rating anchors.
Conclusions
Researchers, clinicians, and healthcare policy decision makers can consider using this instrument to evaluate the design, conduct, and analysis of studies estimating anchor based minimal important differences.
Background
Many depressed patients are not able to achieve or sustain symptom remission despite serial treatment trials – often termed “treatment resistant depression”. A broader, perhaps more empathic concept of “difficult-to-treat depression” (DTD) was considered.
Methods
A consensus group discussed the definition, clinical recognition, assessment and management implications of the DTD heuristic.
Results
The group proposed that DTD be defined as “depression that continues to cause significant burden despite usual treatment efforts”. All depression management should include a thorough initial assessment. When DTD is recognized, a regular reassessment that employs a multi-dimensional framework to identify addressable barriers to successful treatment (including patient-, illness- and treatment-related factors) is advised, along with specific recommendations for addressing these factors. The emphasis of treatment, in the first instance, shifts from a goal of remission to optimal symptom control, daily psychosocial functional and quality of life, based on a patient-centred approach with shared decision-making to enhance the timely consideration of all treatment options (including pharmacotherapy, psychotherapy, neurostimulation, etc.) to optimize outcomes when sustained remission is elusive.
Limitations
The recommended definition and management of DTD is based largely on expert consensus. While DTD would seem to have clinical utility, its specificity and objectivity may be insufficient to define clinical populations for regulatory trial purposes, though DTD could define populations for service provision or phase 4 trials.
Conclusions
DTD provides a clinically useful conceptualization that implies a search for and remediation of specific patient-, illness- and treatment obstacles to optimizing outcomes of relevance to patients.
Current medication for anxiety disorders is suboptimal in terms of efficiency and tolerability, highlighting the need for improved drug treatments. In this review an overview of drugs being studied in different phases of clinical trials for their potential in the treatment of fear-, anxiety- and trauma-related disorders is presented. One strategy followed in drug development is refining and improving compounds interacting with existing anxiolytic drug targets, such as serotonergic and prototypical GABAergic benzodiazepines. A more innovative approach involves the search for compounds with novel mechanisms of anxiolytic action using the growing knowledge base concerning the relevant neurocircuitries and neurobiological mechanisms underlying pathological fear and anxiety. The target systems evaluated in clinical trials include glutamate, endocannabinoid and neuropeptide systems, as well as ion channels and targets derived from phytochemicals. Examples of promising novel candidates currently in clinical development for generalised anxiety disorder, social anxiety disorder, panic disorder, obsessive compulsive disorder or post-traumatic stress disorder include ketamine, riluzole, xenon with one common pharmacological action of modulation of glutamatergic neurotransmission, as well as the neurosteroid aloradine. Finally, compounds such as D-cycloserine, MDMA, L-DOPA and cannabinoids have shown efficacy in enhancing fear-extinction learning in humans. They are thus investigated in clinical trials as an augmentative strategy for speeding up and enhancing the long-term effectiveness of exposure-based psychotherapy, which could render chronic anxiolytic drug treatment dispensable for many patients. These efforts are indicative of a rekindled interest and renewed optimism in the anxiety drug discovery field, after decades of relative stagnation.
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.
Introduction
Appendicitis is a global disease affecting roughly 1 in every 12 people in the world, with the highest incidence between ages 10 and 19 years. To date, a wide variety of health outcomes have been reported in randomised controlled trials and meta-analyses evaluating treatments for appendicitis. This is especially the case in studies comparing non-operative treatment with operative treatment. A set of standard outcomes, to be reported in all future trials, is needed to allow for adequate comparison and interpretation of clinical trial results and to make data pooling possible. This protocol describes the development of such a global core outcome set (COS) to allow unified reporting of treatment interventions in children with acute uncomplicated appendicitis.
Methods and analysis
We use current international standard methodology for the development and reporting of this COS. Its development consists of three phases: (1) an update of the most recent systematic review on outcomes reported in uncomplicated paediatric appendicitis research to identify additional outcomes, (2) a three-step global Delphi study to identify a set of core outcomes for which there is consensus between parents and (paediatric) surgeons and (3) an expert meeting to finalise the COS and its definitions. Children and young people will be involved through their parents during phase 2 and will be engaged directly using a customised face-to-face approach.
Ethics and dissemination
The medical research ethics committee of the Academic Medical Center Amsterdam has approved the study. Each participating country/research group will ascertain ethics board approval. Electronic informed consent will be obtained from all participants. Results will be presented in peer-reviewed academic journals and at (international) conferences.
Trial registration number
COMET registration: 1119
As the challenge of mental health problems such as anxiety and depression increasing today, more convenient, objective, real-time assessing techniques of mental state are in need. The Microsoft Kinect camera is a possible option for contactlessly capturing human gait, which could reflect the walkers’ mental state. So we tried to propose a novel method for monitoring individual’s anxiety and depression based on the Kinect-recorded gait pattern. In this study, after finishing the 7-item Generalized Anxiety Disorder Scale (GAD-7) and the 9-item Patient Health Questionnaire (PHQ-9), 179 participants were required to walked on the footpath naturally while shot by the Kinect cameras. Fast Fourier Transforms (FFT) were conducted to extract features from the Kinect-captured gait data after preprocessing, and different machine learning algorithms were used to train the regression models recognizing anxiety and depression levels, and the classification models detecting the cases with specific depressive symptoms. The predictive accuracies of the regression models achieved medium to large level: The correlation coefficient between predicted and questionnaire scores reached 0.51 on anxiety (by epsilon-Support Vector Regression, e-SVR) and 0.51 on depression (by Gaussian Processes, GP). The predictive accuracies could be even higher, 0.74 on anxiety (by GP) and 0.64 on depression (by GP), while training and testing the models on the female sample. The classification models also showed effectiveness on detecting the cases with some symptoms. These results demonstrate the possibility to recognize individual’s questionnaire measured anxiety/depression levels and some depressive symptoms based on Kinect-recorded gait data through machine learning method. This approach shows the potential to develop non-intrusive, low-cost methods for monitoring individuals’ mental health in real time.
Objectives
The Delphi method is commonly used to achieve consensus in core outcome set (COS) development. It is important to try to maximize response rates to Delphi studies and minimize attrition rates and potential for bias. The factors that impact response rates in a Delphi study used for COS development are unknown. The objective of this study was to explore the impact of design characteristics on response rates in Delphi surveys within COS development.
Methods
Published and ongoing studies that included Delphi to develop a COS were eligible. Second round voting response rates were analyzed, and multilevel linear regression was conducted to investigate whether design characteristics were associated with the response rate.
Results
Thirty-one studies were included. Two characteristics were significantly associated with a lower response rate: larger panels and studies with more items included.
Conclusion
COS developers should pay attention to methods when designing a COS development study; in particular, the size of the panels and the size of the list of outcomes. We identified other potential design characteristics that might influence response rates but were unable to explore them in this analysis. These should be reported in future reports to allow for further investigation.
Importance
Biologic systems involved in the regulation of motor activity are intricately linked with other homeostatic systems such as sleep, feeding behavior, energy, and mood. Mobile monitoring technology (eg, actigraphy and ecological momentary assessment devices) allows the assessment of these multiple systems in real time. However, most clinical studies of mental disorders that use mobile devices have not focused on the dynamic associations between these systems.
Objectives
To examine the directional associations among motor activity, energy, mood, and sleep using mobile monitoring in a community-identified sample, and to evaluate whether these within-day associations differ between people with a history of bipolar or other mood disorders and controls without mood disorders.
Design, Setting, and Participants
This study used a nested case-control design of 242 adults, a subsample of a community-based sample of adults. Probands were recruited by mail from the greater Washington, DC, metropolitan area from January 2005 to June 2013. Enrichment of the sample for mood disorders was provided by volunteers or referrals from the National Institutes of Health Clinical Center or by participants in the National Institute of Mental Health Mood and Anxiety Disorders Program. The inclusion criteria were the ability to speak English, availability to participate, and consent to contact at least 2 living first-degree relatives. Data analysis was performed from June 2013 through July 2018.
Main Outcomes and Measures
Motor activity and sleep duration data were obtained from minute-to-minute activity counts from an actigraphy device worn on the nondominant wrist for 2 weeks. Mood and energy levels were assessed by subjective analogue ratings on the ecological momentary assessment (using a personal digital assistant) by participants 4 times per day for 2 weeks.
Results
Of the total 242 participants, 92 (38.1%) were men and 150 (61.9%) were women, with a mean (SD) age of 48 (16.9) years. Among the participants, 54 (22.3%) had bipolar disorder (25 with bipolar I; 29 with bipolar II), 91 (37.6%) had major depressive disorder, and 97 (40.1%) were controls with no history of mood disorders. A unidirectional association was found between motor activity and subjective mood level (β = –0.018, P = .04). Bidirectional associations were observed between motor activity (β = 0.176; P = .03) and subjective energy level (β = 0.027; P = .03) as well as between motor activity (β = –0.027; P = .04) and sleep duration (β = –0.154; P = .04). Greater cross-domain reactivity was observed in bipolar disorder across all outcomes, including motor activity, sleep, mood, and energy.
Conclusions and Relevance
These findings suggest that interventions focused on motor activity and energy may have greater efficacy than current approaches that target depressed mood; both active and passive tracking of multiple regulatory systems are important in designing therapeutic targets.
Background:
'Big data' has great potential to help address the global health challenge of obesity. However, lack of clarity with regard to the definition of big data and frameworks for effectively using big data in the context of obesity research may be hindering progress. The aim of this study was to establish agreed approaches for the use of big data in obesity-related research.
Methods:
A Delphi method of consensus development was used, comprising three survey rounds. In Round 1, participants were asked to rate agreement/disagreement with 77 statements across seven domains relating to definitions of, and approaches to, using big data in the context of obesity research. Participants were also asked to contribute further ideas in relation to these topics, which were incorporated as new statements (n = 8) in Round 2. In Rounds 2 and 3 participants re-appraised their ratings in view of the group consensus.
Results:
Ninety-six experts active in obesity-related research were invited to participate. Of these, 36/96 completed Round 1 (37.5% response rate), 29/36 completed Round 2 (80.6% response rate) and 26/29 completed Round 3 (89.7% response rate). Consensus (defined as > 70% agreement) was achieved for 90.6% (n = 77) of statements, with 100% consensus achieved for the Definition of Big Data, Data Governance, and Quality and Inference domains.
Conclusions:
Experts agreed that big data was more nuanced than the oft-cited definition of 'volume, variety and velocity', and includes quantitative, qualitative, observational or intervention data from a range of sources that have been collected for research or other purposes. Experts repeatedly called for third party action, for example to develop frameworks for reporting and ethics, to clarify data governance requirements, to support training and skill development and to facilitate sharing of big data. Further advocacy will be required to encourage organisations to adopt these roles.
Objective
To provide practical clinical guidance for the treatment of adults with panic disorder, social anxiety disorder and generalised anxiety disorder in Australia and New Zealand.
Method
Relevant systematic reviews and meta-analyses of clinical trials were identified by searching PsycINFO, Medline, Embase and Cochrane databases. Additional relevant studies were identified from reference lists of identified articles, grey literature and literature known to the working group. Evidence-based and consensus-based recommendations were formulated by synthesising the evidence from efficacy studies, considering effectiveness in routine practice, accessibility and availability of treatment options in Australia and New Zealand, fidelity, acceptability to patients, safety and costs. The draft guidelines were reviewed by expert and clinical advisors, key stakeholders, professional bodies, and specialist groups with interest and expertise in anxiety disorders.
Results
The guidelines recommend a pragmatic approach beginning with psychoeducation and advice on lifestyle factors, followed by initial treatment selected in collaboration with the patient from evidence-based options, taking into account symptom severity, patient preference, accessibility and cost. Recommended initial treatment options for all three anxiety disorders are cognitive–behavioural therapy (face-to-face or delivered by computer, tablet or smartphone application), pharmacotherapy (a selective serotonin reuptake inhibitor or serotonin and noradrenaline reuptake inhibitor together with advice about graded exposure to anxiety triggers), or the combination of cognitive–behavioural therapy and pharmacotherapy.
Conclusion
The Royal Australian and New Zealand College of Psychiatrists clinical practice guidelines for the treatment of panic disorder, social anxiety disorder and generalised anxiety disorder provide up-to-date guidance and advice on the management of these disorders for use by health professionals in Australia and New Zealand.
Background:
Promoting the collection and use of health related outcome measures (HROM) in daily practice has long been a goal for improving and assessing the effectiveness of care provided to patients. However, there has been a lack of consensus on what criteria to use to select outcomes or instruments, particularly in the context of primary health care settings where patients present with multiple concurrent health conditions and interventions are whole-health and person-focused. The purpose of this proposed study is to undertake a formal consensus exercise to establish criteria for selecting HROM (including patient-reported (PRO or PROM), observer-reported (ObsR)), clinician-reported (ClinRO) and performance related outcomes (PerfO) for use in shared decision-making, or in assessing, screening or monitoring health status in primary health care settings.
Methods:
A Delphi consensus online survey will be developed. Criteria for the Delphi panel participants to consider were selected from a targeted literature search. These initial criteria (n = 35) were grouped into four categories within which items will be presented in the Delphi survey, with the option to suggest additional items. Panel members invited to participate will include primary health care practitioners and administrators, policy-makers, researchers, and experts in HROM development; patients will be excluded. Standard Delphi methodology will be employed with an expectation of at least 3 rounds to achieve consensus (75% agreement). As the final list of criteria for selecting HROM emerges, panel members will be asked to provide opinions about potential weighting of items. The Delphi survey was approved by the Ethics Committee in the Faculty of Health Sciences at McMaster University.
Discussion:
Previous literature establishing criteria for selecting HROM were developed with a focus on patient reported outcomes, psychological/ behavioural outcomes or outcomes for minimum core outcome sets in clinical trials. Although helpful, these criteria may not be applicable and feasible for application in a primary health care context where patients with multi-morbidity and complex interventions are typical and the constraints of providing health services differ from those in research studies. The findings from this Delphi consensus study will address a gap for establishing consensus on criteria for selecting HROM for use across primary health care settings.
Objective:
The aim of the present study was to provide clinical consensus and evidence regarding initial treatment strategies for the pharmacological treatment of social anxiety disorder (SAD) in Korea.
Methods:
We prepared a questionnaire to derive a consensus from clinicians regarding their preference for the pharmacological treatment of SAD in Korea. Data regarding medication regimens and psychotropic drugs used during initial treatment, the doses used, and the pharmacological treatment duration were obtained. Responses were obtained from 66 SAD experts, and their opinions were classified into three categories (first-line, second-line, third-line) using a chi-square analysis.
Results:
Clinicians agreed upon first-line regimens for SAD involving monotherapy with selective serotonin reuptake inhibitors (SSRIs) or the serotonin-norepinephrine reuptake inhibitor (SNRI) venlafaxine, or combined therapy using antidepressants with betablockers or benzodiazepines on a standing or as-needed basis. First-line psychotropic drug choices for initial treatment included the following: escitalopram, paroxetine, sertraline, venlafaxine, and propranolol. The medication dosage used by domestic clinicians was found to be comparable with foreign guidelines. Domestic clinicians tended to make treatment decisions in a shorter amount of time and preferred a similar duration of maintenance treatment for SAD when compared with foreign clinicians.
Conclusion:
This study may provide significant information for developing SAD pharmacotherapy guidelines in Korea, especially in the early stage of treatment.
Objective
To define a standard set of outcomes and the most appropriate instruments to measure them for managing newly diagnosed patients with multiple myeloma (MM).
Methods
A literature review and five discussion groups facilitated the design of two-round Delphi questionnaire. Delphi panellists (haematologists, hospital pharmacists and patients) were identified by the scientific committee, the Spanish Program of Haematology Treatments Foundation, the Spanish Society of Hospital Pharmacies and the Spanish Community of Patients with MM. Panellist’s perception about outcomes’ suitability and feasibility of use was assessed on a seven-point Likert scale. Consensus was reached when at least 75% of the respondents reached agreement or disagreement. A scientific committee led the project.
Results
Fifty-one and 45 panellists participated in the first and second Delphi rounds, respectively. Consensus was reached to use overall survival, progression-free survival, minimal residual disease and treatment response to assess survival and disease control. Panellists agreed to measure health-related quality of life, pain, performance status, fatigue, psychosocial status, symptoms, self-perception on body image, sexuality and preferences/satisfaction. However, panellist did not reach consensus about the feasibility of assessing in routine practice psychosocial status, symptoms, self-perception on body image and sexuality. Consensus was reached to collect patient-reported outcomes through the European Organisation for the Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) Core questionnaire 30 (C30), three items from EORTC-QLQ-Multiple Myeloma (MY20) and EORTC-QLQ-Breast Cancer (BR23), pain Visual Analogue Scale, Morisky-Green and ad hoc questions about patients’ preferences/satisfaction.
Conclusions
A consensual standard set of outcomes for managing newly diagnosed patients with MM has been defined. The feasibility of its implementation in routine practice will be assessed in a future pilot study.
Despite considerable progress in pharmacotherapy over the past seven decades, many mental disorders remain insufficiently treated. This situation is in part due to the limited knowledge of the pathophysiology of these disorders and the lack of biological markers to stratify and individualize patient selection, but also to a still restricted number of mechanisms of action being targeted in monotherapy or combination/augmentation treatment, as well as to a variety of challenges threatening the successful development and testing of new drugs. In this paper, we first provide an overview of the most promising drugs with innovative mechanisms of action that are undergoing phase 2 or 3 testing for schizophrenia, bipolar disorder, major depressive disorder, anxiety and trauma‐related disorders, substance use disorders, and dementia. Promising repurposing of established medications for new psychiatric indications, as well as variations in the modulation of dopamine, noradrenaline and serotonin receptor functioning, are also considered. We then critically discuss the clinical trial parameters that need to be considered in depth when developing and testing new pharmacological agents for the treatment of mental disorders. Hurdles and perils threatening success of new drug development and testing include inadequacy and imprecision of inclusion/exclusion criteria and ratings, sub‐optimally suited clinical trial participants, multiple factors contributing to a large/increasing placebo effect, and problems with statistical analyses. This information should be considered in order to de‐risk trial programmes of novel agents or known agents for novel psychiatric indications, increasing their chances of success.
Importance
Anxiety disorders are common, highly distressing, and impairing conditions. Effective treatments exist, but many patients do not access or respond to them. Mindfulness-based interventions, such as mindfulness-based stress reduction (MBSR) are popular and can decrease anxiety, but it is unknown how they compare to standard first-line treatments.
Objective
To determine whether MBSR is noninferior to escitalopram, a commonly used first-line psychopharmacological treatment for anxiety disorders.
Design, Setting, and Participants
This randomized clinical trial (Treatments for Anxiety: Meditation and Escitalopram [TAME]) included a noninferiority design with a prespecified noninferiority margin. Patients were recruited between June 2018 and February 2020. The outcome assessments were performed by blinded clinical interviewer at baseline, week 8 end point, and follow-up visits at 12 and 24 weeks. Of 430 individuals assessed for inclusion, 276 adults with a diagnosed anxiety disorder from 3 urban academic medical centers in the US were recruited for the trial, and 208 completed the trial.
Interventions
Participants were 1:1 randomized to 8 weeks of the weekly MBSR course or the antidepressant escitalopram, flexibly dosed from 10 to 20 mg.
Main Outcomes and Measures
The primary outcome measure was anxiety levels as assessed with the Clinical Global Impression of Severity scale (CGI-S), with a predetermined noninferiority margin of −0.495 points.
Results
The primary noninferiority sample consisted of 208 patients (102 in MBSR and 106 in escitalopram), with a mean (SD) age of 33 (13) years; 156 participants (75%) were female; 32 participants (15%) were African American, 41 (20%) were Asian, 18 (9%) were Hispanic/Latino, 122 (59%) were White, and 13 (6%) were of another race or ethnicity (including Native American or Alaska Native, more than one race, or other, consolidated owing to low numbers). Baseline mean (SD) CGI-S score was 4.44 (0.79) for the MBSR group and 4.51 (0.78) for the escitalopram group in the per-protocol sample and 4.49 (0.77) vs 4.54 (0.83), respectively, in the randomized sample. At end point, the mean (SD) CGI-S score was reduced by 1.35 (1.06) for MBSR and 1.43 (1.17) for escitalopram. The difference between groups was −0.07 (0.16; 95% CI, −0.38 to 0.23; P = .65), where the lower bound of the interval fell within the predefined noninferiority margin of −0.495, indicating noninferiority of MBSR compared with escitalopram. Secondary intent-to-treat analyses using imputed data also showed the noninferiority of MBSR compared with escitalopram based on the improvement in CGI-S score. Of patients who started treatment, 10 (8%) dropped out of the escitalopram group and none from the MBSR group due to adverse events. At least 1 study-related adverse event occurred for 110 participants randomized to escitalopram (78.6%) and 21 participants randomized to MBSR (15.4%).
Conclusions and Relevance
The results from this randomized clinical trial comparing a standardized evidence-based mindfulness-based intervention with pharmacotherapy for the treatment of anxiety disorders found that MBSR was noninferior to escitalopram.
Trial Registration
ClinicalTrials.gov Identifier: NCT03522844
Aim: This is the third version of the guideline of the World Federation of Societies of Biological Psychiatry (WFSBP) Task Force for the Pharmacological Treatment of Anxiety, Obsessive-Compulsive and Posttraumatic Stress Disorders which was published in 2002 and revised in 2008.Method: A consensus panel of 34 international experts representing 22 countries developed recommendations based on efficacy and acceptability of the treatments. In this version, not only medications but also psychotherapies and other non-pharmacological interventions were evaluated, applying the same rigorous methods that are standard for the assessment of medication treatments.Result: The present paper (Part II) contains recommendations based on published randomised controlled trials (RCTs) for the treatment of OCD (n = 291) and PTSD (n = 234) in children, adolescents, and adults. The accompanying paper (Part I) contains the recommendations for the treatment of anxiety disorders.For OCD, first-line treatments are selective serotonin reuptake inhibitors (SSRIs) and cognitive behavioural therapy (CBT). Internet-CBT was also superior to active controls. Several second-line medications are available, including clomipramine. For treatment-resistant cases, several options are available, including augmentation of SSRI treatment with antipsychotics and other drugs.Other non-pharmacological treatments, including repetitive transcranial magnetic stimulation (rTMS), deep brain stimulation (DBS) and others were also evaluated.For PTSD, SSRIs and the SNRI venlafaxine are first-line treatments. CBT is the psychotherapy modality with the best body of evidence. For treatment-unresponsive patients, augmentation of SSRI treatment with antipsychotics may be an option.Conclusion: OCD and PTSD can be effectively treated with CBT and medications.
Aim:
This is the third version of the guideline of the World Federation of Societies of Biological Psychiatry (WFSBP) Task Force for the Pharmacological Treatment of Anxiety, Obsessive-Compulsive and Posttraumatic Stress Disorders (published in 2002, revised in 2008).
Method:
A consensus panel of 33 international experts representing 22 countries developed recommendations based on efficacy and acceptability of available treatments. In total, 1007 RCTs for the treatment of these disorders in adults, adolescents, and children with medications, psychotherapy and other non-pharmacological interventions were evaluated, applying the same rigorous methods that are standard for the assessment of medications.
Result:
This paper, Part I, contains recommendations for the treatment of panic disorder/agoraphobia (PDA), generalised anxiety disorder (GAD), social anxiety disorder (SAD), specific phobias, mixed anxiety disorders in children and adolescents, separation anxiety and selective mutism. Selective serotonin reuptake inhibitors (SSRI) and serotonin-norepinephrine reuptake inhibitors (SNRIs) are first-line medications. Cognitive behavioural therapy (CBT) is the first-line psychotherapy for anxiety disorders. The expert panel also made recommendations for patients not responding to standard treatments and recommendations against interventions with insufficient evidence.
Conclusion:
It is the goal of this initiative to provide treatment guidance for these disorders that has validity throughout the world.
Background
Social Anxiety Disorder (SAD) or Social Phobia is characterized by fear and anxiety of social circumstances that negatively impact an individuals' occupational and relational life. There are several treatment options for this disorder ranging from pharmacological therapy to psychotherapies. In particular, the Acceptance and Commitment Therapy (ACT), a form of cognitive-behavioral therapy that practices acceptance and awareness strategies with behavior change strategies in order to increase an individual's mental flexibility, has been found to be effective. Therefore, we aimed to provide an overview of recent studies that examined ACT's efficacy in SAD, also taking into consideration the comparison with traditional Cognitive-behavioral Therapy (CBT) interventions.
Methods
A bibliographic search on PubMed, EMBASE and Scopus was conducted from inception to the 3rd of February 2022 of all studies investigating the effect of ACT in SAD individuals without any comorbidity. Among the articles retrieved, 11 met the inclusion criteria.
Results
From the reviewed studies, ACT may be considered a promising treatment of social phobia by improving attentional bias, awareness, emotion regulation, and safety/avoidance behaviors; however, the results have not yet demonstrated a valid alternative to the CBT.
Limitations
Only four studies considered a follow-up evaluation, which is paramount to exploring the effectiveness of ACT and several studies have a very small sample size. Concerning the review itself we only considered original English articles and we did not measure the risk of publication bias and the risk of bias between studies.
Conclusions
The results of this study suggest that ACT can be a promising treatment for improving selective psychological problems often observed in SAD. However, larger longitudinal studies further exploring the effectiveness of the behavioral and cognitive “third-wave” psychotherapies, based mainly on acceptance of SAD are necessary.
Objective
This review aimed to measure the degree of placebo response in panic disorder.
Data Sources
We searched major databases up to 31 January 2021, for randomized pharmacotherapy trials published in English.
Study Selection
A total of 43 studies met inclusion criteria to be in the analysis (with 174 separate outcome measurements).
Data Extraction
Changes in outcome measures from baseline in the placebo group were used to estimate modified Cohen’s d effect size.
Results
A total of 43 trials (2392 subjects, 174 outcomes using 27 rating scales) were included in the meta-analysis. Overall placebo effect size was 0.57 (95% confidence interval = [0.50, 0.64]), heterogeneity ( I ² : 96.3%). Higher placebo effect size was observed among clinician-rated scales compared to patient reports (0.75 vs 0.35) and among general symptom and anxiety scales compared to panic symptoms and depression scales (0.92 and 0.64 vs 0.56 and 0.54, respectively). There was an upward trend in effect size over the publication period ( r = 0.02, p = 0.002) that was only significant among clinician-rated scales ( r = 0.02, p = 0.011). There was no significant publication bias, Egger’s test ( p = 0.08).
Conclusion
We observed a substantial placebo effect size in panic disorder. This effect was more prominent for some aspects of panic disorder psychopathology than for others and was correlated with the source of the assessment and publication year. This finding has implications both for research design, to address the heterogeneity and diversity in placebo responses, and for clinical practice to ensure optimal quality of care.
Systematic review registration number
PROSPERO, CRD42019125979.
Background
In longitudinal research, switching between diagnoses should be considered when examining patients with depression and anxiety. We investigated course trajectories of affective disorders over a nine-year period, comparing a categorical approach using diagnoses to a dimensional approach using symptom severity.
Method
Patients with a current depressive and/or anxiety disorder at baseline (N = 1701) were selected from the Netherlands Study of Depression and Anxiety (NESDA). Using psychiatric diagnoses, we described ‘consistently recovered,’ ‘intermittently recovered, ‘intermittently recurrent’, and ‘consistently chronic’ at two-, four-, six-, and nine-year follow-up. Additionally, latent class growth analysis (LCGA) using depressive, anxiety, fear, and worry symptom severity scores was used to identify distinct classes.
Results
Considering the categorical approach, 8.5% were chronic, 32.9% were intermittently recurrent, 37.6% were intermittently recovered, and 21.0% remained consistently recovered from any affective disorder at nine-year follow-up. In the dimensional approach, 66.6% were chronic, 25.9% showed partial recovery, and 7.6% had recovered.
Limitations
30.6% of patients were lost to follow-up. Diagnoses were rated by the interviewer and questionnaires were completed by the participant.
Conclusions
Using diagnoses alone as discrete categories to describe clinical course fails to fully capture the persistence of affective symptoms that were observed when using a dimensional approach. The enduring, fluctuating presence of subthreshold affective symptoms likely predisposes patients to frequent relapse. The commonness of subthreshold symptoms and their adverse impact on long-term prognoses deserve continuous clinical attention in mental health care as well further research.
Background
Treatment resistance in anxiety disorders (TR-AD) has been previously defined by failed priortreatments and by various clinical aspects, but the impact of these aspects on course duringsubsequent treatments was never studied. Moreover, TR-AD was never studied using a dimensionalapproach. This study validated aspects of TR-AD and examined whether a TR-AD score was relatedto two-year course during treatment.
Method
From the NESDA cohort, anxiety disorder patients who subsequently received treatment wereselected (n=679). Literature-derived aspects of TR-AD at baseline included anxiety severity, functionalimpairments, psychiatric comorbidity, duration, and previous treatments. These were combined into adimensional TR-AD score. Individual aspects of TR-AD and the TR-AD score were linked to anxietydisorder persistence at two-year follow-up using logistic regression analyses. Predictive properties forthe TR-AD score were assessed.
Results
Current symptom severity, psychiatric comorbidity, functional impairments and previous duration ofsymptoms were closely associated with two-year anxiety disorder persistence, while treatment historywas not. The TR-AD score (10.8±2.3, range 2-23) was linked to two-year persistence (OR per pointincrement 1.29, p<0.01). The predictive properties of the TR-AD score appeared modest (AUC=0.66).
Limitations
In the current study, treatment history and ongoing treatments were retrospectively assessed. It wasnot evaluated whether prior treatments failed or succeeded.
Conclusions
The results in the current study suggest that when assessing TR-AD and designing a treatment plan,evaluations of treatment history should be accompanied with assessments of clinical characteristics.The dimensional TR-AD measurement presented here could be used for this purpose.
Anxiety disorders form the most common group of mental disorders and generally start before or in early adulthood. Core features include excessive fear and anxiety or avoidance of perceived threats that are persistent and impairing. Anxiety disorders involve dysfunction in brain circuits that respond to danger. Risk for anxiety disorders is influenced by genetic factors, environmental factors, and their epigenetic relations. Anxiety disorders are often comorbid with one another and with other mental disorders, especially depression, as well as with somatic disorders. Such comorbidity generally signifies more severe symptoms, greater clinical burden, and greater treatment difficulty. Reducing the large burden of disease from anxiety disorders in individuals and worldwide can be best achieved by timely, accurate disease detection and adequate treatment administration, scaling up of treatments when needed. Evidence-based psychotherapy (particularly cognitive behavioural therapy) and psychoactive medications (particularly serotonergic compounds) are both effective, facilitating patients' choices in therapeutic decisions. Although promising, no enduring preventive measures are available, and, along with frequent therapy resistance, clinical needs remain unaddressed. Ongoing research efforts tackle these problems, and future efforts should seek individualised, more effective approaches for treatment with precision medicine.
Anxiety disorders are among the most common psychiatric disorders in children and adolescents. As reviewed in this guideline, both cognitive behavioral therapy (CBT) and selective serotonin reuptake inhibitor (SSRI) medication have considerable empirical support as safe and effective short-term treatments for anxiety in children and adolescents. Serotonin norepinephrine reuptake inhibitor (SNRI) medication has some empirical support as an additional treatment option. In the context of a protracted severe shortage of child and adolescent-trained behavioral health specialists, research demonstrating convenient, efficient, cost-effective, and user-friendly delivery mechanisms for safe and effective treatments for child and adolescent anxiety disorders is an urgent priority. The comparative effectiveness of anxiety treatments, delineation of mediators and moderators of effective anxiety treatments, long-term effects of SSRI and SNRI use in children and adolescents, and additional evaluation of the degree of suicide risk associated with SSRIs and SNRIs, remain other key research needs.
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.
In the DSM-5, separation anxiety disorder (SAD) is newly classified in the chapter on anxiety, renewing research efforts into its etiology. In this narrative review, we summarize the current literature on the genetic, endocrine, physiological, neural and neuropsychological underpinnings of SAD per se, SAD in the context of panic disorder, separation anxiety symptoms, and related intermediate phenotypes.
SAD aggregates in families and has a heritability of ~43%. Variants in the oxytocin receptor, serotonin transporter, opioid receptor µ1, dopamine D4 receptor and translocator protein genes have all been associated with SAD. Dysregulation of the hypothalamus-pituitary-adrenal axis, dysfunctional cortico-limbic interaction and biased cognitive processing seem to constitute further neurobiological markers of separation anxiety. Hypersensitivity to carbon dioxide appears to be an endophenotype shared by SAD, panic disorder and anxiety sensitivity.
The identification of biological risk markers and its multi-level integration hold great promise regarding the prediction of SAD risk, maintenance and course, and in the future may allow for the selection of indicated preventive and innovative, personalized therapeutic interventions.
Background:
Non-responsiveness to treatment occurs in approximately one third of patients. Randomized clinical trials of psychotherapy options for these patients are scarce and systematic knowledge about whether psychotherapy is a viable option is lacking.
Objectives:
This meta-analysis aimed to 1) determine the amount of evidence available for treatment non-response using psychotherapy relative to pharmacological procedures; 2) systematically review randomized controlled psychotherapy trials (RCTs) used to treat non-responders; and 3) examine whether some psychotherapies are more efficacious than others.
Data sources:
Online databases were systematically examined and references of relevant systematic reviews were hand-searched.
Study eligibility criteria:
RCTs that administered a psychotherapy new to non-responders were considered. All Mood and Anxiety Disorders were considered. No limitations were made with respect to type of treatment.
Review method:
A meta-analytic review of the psychotherapy RCTs for treatment non-responders.
Results:
Results showed that psychotherapy was successful in treating treatment non-responders with a medium to large effect size. Between-group comparisons did not reveal significant differences in treatment effects for any of the assessed disorder or treatment types. Effects were maintained at follow-up.
Conclusions:
Psychotherapy is a viable treatment option for treatment non-responders. More attention to this group of patients is needed and more research with better quality studies is warranted. Recommendations are discussed.
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.
Currently there is no universally accepted definition of remission in anxiety disorders. This may be causing significantly different estimates of treatment efficacy across anxiety disorders. The aim of this paper was to determine not only the overall remission rate in cognitive-behavioral therapy (CBT) for anxiety disorders, but also to examine whether the different definitions of remission lead to significantly different remission rates. From the initial 228 abstracts reviewed by the authors, 100 articles were retained. The overall mean remission rate was 51.0%. Remission rates were highest when remission was defined as good end state functioning or no longer meeting criteria for the primary diagnosis. Studies of posttraumatic stress disorder had the highest remission rates, while those of obsessive-compulsive disorder and social anxiety disorder had the lowest remission rates. Rates of remission differed by certain demographic (e.g., older age) and clinical (e.g., medication use) characteristics. Although CBT is an empirically supported treatment for anxiety disorders, it is clear that there is room for improvement, as many patients do not achieve remission status.