[Anxiety]. / Angst.

In this article, we will address 10 questions about anxiety that are relevant to doctors who encounter this in their practice. This often occurs in the primary care setting, where individuals with anxiety frequently present with somatic complaints. A focused medical history, including questions about the use and withdrawal of psychoactive substances, can assist in the diagnostic process. Psychoeducation may be sufficient, otherwise cognitive-behavioral therapy can be conducted. In cases of non-response, serotonergic antidepressants represent a treatment option. Half of the individuals with anxiety symptoms experience remission, while the other half have a recurrent or chronic course, which may be accompanied by comorbid depression.

Impact of hemodilution on flow cytometry based measurable residual disease assessment in acute myeloid leukemia.

Measurable residual disease (MRD) measured in the bone marrow (BM) of acute myeloid leukemia (AML) patients after induction chemotherapy is an established prognostic factor. Hemodilution, stemming from peripheral blood (PB) mixing within BM during aspiration, can yield false-negative MRD results. We prospectively examined hemodilution by measuring MRD in BM aspirates obtained from three consecutive 2 mL pulls, along with PB samples. Our results demonstrated a significant decrease in MRD percentages between the first and second pulls (P = 0.025) and between the second and third pulls (P = 0.025), highlighting the impact of hemodilution. Initially, 39% of MRD levels (18/46 leukemia-associated immunophenotypes) exceeded the 0.1% cut-off, decreasing to 30% (14/46) in the third pull. Additionally, we assessed the performance of six published methods and parameters for distinguishing BM from PB samples, addressing or compensating for hemodilution. The most promising results relied on the percentages of CD16dim granulocytic population (scarce in BM) and CD117high mast cells (exclusive to BM). Our findings highlight the importance of estimating hemodilution in MRD assessment to qualify MRD results, particularly near the common 0.1% cut-off. To avoid false-negative results by hemodilution, it is essential to collect high-quality BM aspirations and preferably utilizing the initial pull for MRD testing.

Baseline Severity as a Moderator of the Waiting List-Controlled Association of Cognitive Behavioral Therapy With Symptom Change in Social Anxiety Disorder: A Systematic Review and Individual Patient Data Meta-analysis.

Importance: Social anxiety disorder (SAD) can be adequately treated with cognitive behavioral therapy (CBT). However, there is a large gap in knowledge on factors associated with prognosis, and it is unclear whether symptom severity predicts response to CBT for SAD. Objective: To examine baseline SAD symptom severity as a moderator of the association between CBT and symptom change in patients with SAD. Data Sources: For this systematic review and individual patient data meta-analysis (IPDMA), PubMed, PsycInfo, Embase, and the Cochrane Library were searched from January 1, 1990, to January 13, 2023. Primary search topics were social anxiety disorder, cognitive behavior therapy, and randomized controlled trial. Study Selection: Inclusion criteria were randomized clinical trials comparing CBT with being on a waiting list and using the Liebowitz Social Anxiety Scale (LSAS) in adults with a primary clinical diagnosis of SAD. Data Extraction and Synthesis: Authors of included studies were approached to provide individual-level data. Data were extracted by pairs of authors following the Preferred Reporting Items for Systematic Reviews and Meta-analyses reporting guideline, and risk of bias was assessed using the Cochrane tool. An IPDMA was conducted using a 2-stage approach for the association of CBT with change in LSAS scores from baseline to posttreatment and for the interaction effect of baseline LSAS score by condition using random-effects models. Main Outcomes and Measures: The main outcome was the baseline to posttreatment change in symptom severity measured by the LSAS. Results: A total of 12 studies including 1246 patients with SAD (mean [SD] age, 35.3 [10.9] years; 738 [59.2%] female) were included in the meta-analysis. A waiting list-controlled association between CBT and pretreatment to posttreatment LSAS change was found (b = -20.3; 95% CI, -24.9 to -15.6; P < .001; Cohen d = -0.95; 95% CI, -1.16 to -0.73). Baseline LSAS scores moderated the differences between CBT and waiting list with respect to pretreatment to posttreatment symptom reductions (b = -0.22; 95% CI, -0.39 to -0.06; P = .009), indicating that individuals with severe symptoms had larger waiting list-controlled symptom reductions after CBT (Cohen d = -1.13 [95% CI, -1.39 to -0.88] for patients with very severe SAD; Cohen d = -0.54 [95% CI, -0.80 to -0.29] for patients with mild SAD). Conclusions and Relevance: In this systematic review and IPDMA, higher baseline SAD symptom severity was associated with greater (absolute but not relative) symptom reductions after CBT in patients with SAD. The findings contribute to personalized care by suggesting that clinicians can confidently offer CBT to individuals with severe SAD symptoms.

Recurrence of anxiety disorders and its predictors in the general population.

BACKGROUND: Anxiety disorders frequently recur in clinical populations, but the risk of recurrence of anxiety disorders is largely unknown in the general population. In this study, recurrence of anxiety and its predictors were studied in a large cohort of the adult general population. METHODS: Baseline, 3-year and 6-year follow-up data were derived from the Netherlands Mental Health Survey and Incidence Study-2 (NEMESIS-2). Respondents (N = 468) who had been in remission for at least a year prior to baseline were included. Recurrence was assessed at 3 and 6 years after baseline, using the Composite International Diagnostic Interview version 3.0. Cumulative recurrence rates were estimated using the number of years since remission of the last anxiety disorder. Furthermore, Cox regression analyses were conducted to investigate predictors of recurrence, using a broad range of putative predictors. RESULTS: The estimated cumulative recurrence rate was 2.1% at 1 year, 6.6% at 5 years, 10.6% at 10 years, and 16.2% at 20 years. Univariate regression analyses predicted a shorter time to recurrence for several variables, of which younger age at interview, parental psychopathology, neuroticism and a current depressive disorder remained significant in the, age and gender-adjusted, multivariable regression analysis. CONCLUSIONS: Recurrence of anxiety disorders in the general population is common and the risk of recurrence extends over a lengthy period of time. In clinical practice, alertness to recurrence, monitoring of symptoms, and quick access to health care in case of recurrence are needed.

Psychological interventions to prevent relapse in anxiety and depression: A systematic review and meta-analysis.

OBJECTIVES: The aim of this review is to establish the effectiveness of psychological relapse prevention interventions, as stand-alone interventions and in combination with maintenance antidepressant treatment (M-ADM) or antidepressant medication (ADM) discontinuation for patients with remitted anxiety disorders or major depressive disorders (MDD). METHODS: A systematic review and a meta-analysis were conducted. A literature search was conducted in PubMed, PsycINFO and Embase for randomised controlled trials (RCTs) comparing psychological relapse prevention interventions to treatment as usual (TAU), with the proportion of relapse/recurrence and/or time to relapse/recurrence as outcome measure. RESULTS: Thirty-six RCTs were included. During a 24-month period, psychological interventions significantly reduced risk of relapse/recurrence for patients with remitted MDD (RR 0.76, 95% CI: 0.68-0.86, p<0.001). This effect persisted with longer follow-up periods, although these results were less robust. Also, psychological interventions combined with M-ADM significantly reduced relapse during a 24-month period (RR 0.76, 95% CI: 0.62-0.94, p = 0.010), but this effect was not significant for longer follow-up periods. No meta-analysis could be performed on relapse prevention in anxiety disorders, as only two studies focused on relapse prevention in anxiety disorders. CONCLUSIONS: In patients with remitted MDD, psychological relapse prevention interventions substantially reduce risk of relapse/recurrence. It is recommended to offer these interventions to remitted MDD patients. Studies on anxiety disorders are needed. SYSTEMATIC REVIEW REGISTRATION NUMBER: PROSPERO 2018: CRD42018103142.

The Effectiveness of Virtual Reality Exposure-Based Cognitive Behavioral Therapy for Severe Anxiety Disorders, Obsessive-Compulsive Disorder, and Posttraumatic Stress Disorder: Meta-analysis.

BACKGROUND: In recent years, virtual reality exposure-based cognitive behavioral therapy (VRE-CBT) has shown good treatment results in (subclinical) anxiety disorders and seems to be a good alternative to exposure in vivo in regular cognitive behavioral therapy (CBT). However, previous meta-analyses on the efficacy of VRE-CBT on anxiety disorders have included studies on specific phobias and subthreshold anxiety; therefore, these results may not be generalizable to patients with more severe and disabling anxiety disorders. OBJECTIVE: The objective of our study is to determine the efficacy of VRE-CBT on more severe anxiety disorders, excluding specific phobias and subthreshold anxiety disorders. Meta-analyses will be conducted to examine the efficacy of VRE-CBT versus waitlist and regular CBT. Our secondary objectives are to examine whether the efficacy differs according to the type of anxiety disorder, type of recruitment, and type of VRE-CBT (virtual reality exposure either with or without regular CBT). Furthermore, attrition in VRE-CBT and CBT will be compared. METHODS: Studies published until August 20, 2020, were retrieved through systematic literature searches in PubMed, PsycINFO, and Embase. We calculated the effect sizes (Hedges g) for the difference between the conditions and their 95% CIs for posttest and follow-up measurements in a random effects model. A separate meta-analysis was performed to compare attrition between the VRE-CBT and CBT conditions. RESULTS: A total of 16 trials with 817 participants were included. We identified 10 comparisons between VRE-CBT and a waitlist condition and 13 comparisons between VRE-CBT and a CBT condition. With regard to risk of bias, information on random sequence generation, allocation concealment, and risk of bias for selective outcome reporting was often absent or unclear. The mean effect size of VRE-CBT compared with waitlist (nco=10) was medium and significant, favoring VRE-CBT (Hedges g=-0.490, 95% CI -0.82 to -0.16; P=.003). The mean effect size of VRE-CBT compared with CBT (nco=13) was small and nonsignificant, favoring CBT (Hedges g=0.083, 95% CI -0.13 to 0.30; P=.45). The dropout rates between VRE-CBT and CBT (nco=10) showed no significant difference (odds ratio 0.79, 95% CI 0.49-1.27; P=.32). There were no indications of small study effects or publication bias. CONCLUSIONS: The results of our study show that VRE-CBT is more effective than waitlist and as effective as CBT in the treatment of more severe anxiety disorders. Therefore, VRE-CBT may be considered a promising alternative to CBT for patients with more severe anxiety disorders. Higher-quality randomized controlled trials are needed to verify the robustness of these findings.

Why we need to evaluate long-term antidepressant use in older patients with depression.

In this commentary, we address current clinical practice of long-term antidepressant use in older adults with depression, and recommend improvements. Compared with younger adults, older adults more frequently use antidepressants in the long term, although they may not always benefit from them, and in spite of an increased risk for adverse events. Unfortunately, evaluations of long-term antidepressant use are sparse, especially in older age groups. To prevent and reduce inappropriate long-term use and adverse events, antidepressant use in older age groups should be regularly evaluated.

Reasons for Participation and Nonparticipation in Psychological Relapse Prevention for Anxiety and Depression: A Qualitative Study.

BACKGROUND: Anxiety and depressive disorders frequently recur, but participation in effective psychological interventions to prevent relapse is limited. The reasons for nonparticipation are largely unknown, hampering successful implementation. The aims of this study were: (1) to investigate reasons why patients with remitted anxiety or depressive disorders refuse cognitive-behavioral therapy relapse prevention interventions (RPIs), (2) to compare these reasons with reasons to participate, and (3) to gain insight into patients' preferences regarding relapse prevention. METHODS: A qualitative study was conducted in which data were gathered from 52 semistructured interviews with patients who either refused or agreed to participate in psychological relapse prevention. The constant comparative method was used. RESULTS: The data showed that those who refused to participate (1) did have knowledge about relapse risks in general, (2) but did not relate this risk to themselves, and therefore, did not feel the need for relapse prevention, or (3) declined to participate for logistical reasons or reasons related to the content of the intervention. Preferences concerning the form and content of RPIs were very diverse. CONCLUSIONS: Psychoeducation on relapse should be provided to patients to help them relate recurrence risks to themselves. RPIs should also be individually tailored.

Evaluation of a Blended Relapse Prevention Program for Anxiety and Depression in General Practice: Qualitative Study.

BACKGROUND: Existing studies have yet to investigate the perspectives of patients and professionals concerning relapse prevention programs for patients with remitted anxiety or depressive disorders in primary care. User opinions should be considered when optimizing the use and implementation of interventions. OBJECTIVE: This study aimed to evaluate the GET READY relapse prevention programs for patients with remitted anxiety or depressive disorders in general practice. METHODS: Semistructured interviews (N=26) and focus group interviews (N=2) with patients and mental health professionals (MHPs) in the Netherlands were performed. Patients with remitted anxiety or depressive disorders and their MHPs who participated in the GET READY study were interviewed individually. Findings from the interviews were tested in focus group interviews with patients and MHPs. Data were analyzed using thematic analysis. RESULTS: Participants were positive about the program because it created awareness of relapse risks. Lack of motivation, lack of recognizability, lack of support from the MHP, and symptom severity (too low or too high) appeared to be limiting factors in the use of the program. MHPs play a crucial role in motivating and supporting patients in relapse prevention. The perspectives of patients and MHPs were largely in accordance, although they had different perspectives concerning responsibilities for taking initiative. CONCLUSIONS: The implementation of the GET READY program was challenging. Guidance from MHPs should be offered for relapse prevention programs based on eHealth. Both MHPs and patients should align their expectations concerning responsibilities in advance to ensure optimal usage. Usage of blended relapse prevention programs may be further enhanced by diagnosis-specific programs and easily accessible support from MHPs. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.1186/s12888-019-2034-6.

Barriers to discontinuing antidepressants in patients with depressive and anxiety disorders: a review of the literature and clinical recommendations.

Use of antidepressants has recently increased, mainly caused by the increase of long-term users. Although evidence-based indications for long-term use are lacking, it is assumed that long-term use is unnecessary or undesirable in some patients. Perceived barriers to discontinuing antidepressants contribute to unnecessary or undesirable long-term use. Identifying barriers prior to, during and following discontinuation may enable strategies to overcome them. This narrative review summarises relevant qualitative and quantitative articles on perceived barriers to discontinuing antidepressants and provides recommendations for clinical practice. We can conclude that implications for clinical practice are diverse and the most important barriers experienced by patients and physicians include the fear of relapse or recurrence, insufficient evaluation and monitoring, withdrawal symptoms, and actual relapse or recurrence.

Applicability and reproducibility of acute myeloid leukaemia stem cell assessment in a multi-centre setting.

Leukaemic stem cells (LSC) have been experimentally defined as the leukaemia-propagating population and are thought to be the cellular reservoir of relapse in acute myeloid leukaemia (AML). Therefore, LSC measurements are warranted to facilitate accurate risk stratification. Previously, we published the composition of a one-tube flow cytometric assay, characterised by the presence of 13 important membrane markers for LSC detection. Here we present the validation experiments of the assay in several large AML research centres, both in Europe and the United States. Variability within instruments and sample processing showed high correlations between different instruments (Rpearson  > 0·91, P < 0·001). Multi-centre testing introduced variation in reported LSC percentages but was found to be below the clinical relevant threshold. Clear gating protocols resulted in all laboratories being able to perform LSC assessment of the validation set. Participating centres were nearly unanimously able to distinguish LSChigh (>0·03% LSC) from LSClow (<0·03% LSC) despite inter-laboratory variation in reported LSC percentages. This study proves that the LSC assay is highly reproducible. These results together with the high prognostic impact of LSC load at diagnosis in AML patients render the one-tube LSC assessment a good marker for future risk classification.

CD34+CD38- leukemic stem cell frequency to predict outcome in acute myeloid leukemia.

Current risk algorithms are primarily based on pre-treatment factors and imperfectly predict outcome in acute myeloid leukemia (AML). We introduce and validate a post-treatment approach of leukemic stem cell (LSC) assessment for prediction of outcome. LSC containing CD34+CD38- fractions were measured using flow cytometry in an add-on study of the HOVON102/SAKK trial. Predefined cut-off levels were prospectively evaluated to assess CD34+CD38-LSC levels at diagnosis (n = 594), and, to identify LSClow/LSChigh (n = 302) and MRDlow/MRDhigh patients (n = 305) in bone marrow in morphological complete remission (CR). In 242 CR patients combined MRD and LSC results were available. At diagnosis the CD34+CD38- LSC frequency independently predicts overall survival (OS). After achieving CR, combining LSC and MRD showed reduced survival in MRDhigh/LSChigh patients (hazard ratio [HR] 3.62 for OS and 5.89 for cumulative incidence of relapse [CIR]) compared to MRDlow/LSChigh, MRDhigh/LSClow, and especially MRDlow/LSClow patients. Moreover, in the NPM1mutant positive sub-group, prognostic value of golden standard NPM1-MRD by qPCR can be improved by addition of flow cytometric approaches. This is the first prospective study demonstrating that LSC strongly improves prognostic impact of MRD detection, identifying a patient subgroup with an almost 100% treatment failure probability, warranting consideration of LSC measurement incorporation in future AML risk schemes.

Comprehensive Protocol to Sample and Process Bone Marrow for Measuring Measurable Residual Disease and Leukemic Stem Cells in Acute Myeloid Leukemia.

Response criteria in acute myeloid leukemia (AML) has recently been re-established, with morphologic examination utilized to determine whether patients have achieved complete remission (CR). Approximately half of the adult patients who entered CR will relapse within 12 months due to the outgrowth of residual AML cells in the bone marrow. The quantitation of these remaining leukemia cells, known as minimal or measurable residual disease (MRD), can be a robust biomarker for the prediction of these relapses. Moreover, retrospective analysis of several studies has shown that the presence of MRD in the bone marrow of AML patients correlates with poor survival. Not only is the total leukemic population, reflected by cells harboring a leukemia associated immune-phenotype (LAIP), associated with clinical outcome, but so is the immature low frequency subpopulation of leukemia stem cells (LSC), both of which can be monitored through flow cytometry MRD or MRD-like approaches. The availability of sensitive assays that enable detection of residual leukemia (stem) cells on the basis of disease-specific or disease-associated features (abnormal molecular markers or aberrant immunophenotypes) have drastically improved MRD assessment in AML. However, given the inherent heterogeneity and complexity of AML as a disease, methods for sampling bone marrow and performing MRD and LSC analysis should be harmonized when possible. In this manuscript we describe a detailed methodology for adequate bone marrow aspirate sampling, transport, sample processing for optimal multi-color flow cytometry assessment, and gating strategies to assess MRD and LSC to aid in therapeutic decision making for AML patients.

Risk of relapse after antidepressant discontinuation in anxiety disorders, obsessive-compulsive disorder, and post-traumatic stress disorder: systematic review and meta-analysis of relapse prevention trials.

Objectives To examine the risk of relapse and time to relapse after discontinuation of antidepressants in patients with anxiety disorder who responded to antidepressants, and to explore whether relapse risk is related to type of anxiety disorder, type of antidepressant, mode of discontinuation, duration of treatment and follow-up, comorbidity, and allowance of psychotherapy.Design Systematic review and meta-analyses of relapse prevention trials.Data sources PubMed, Cochrane, Embase, and clinical trial registers (from inception to July 2016).Study selection Eligible studies included patients with anxiety disorder who responded to antidepressants, randomised patients double blind to either continuing antidepressants or switching to placebo, and compared relapse rates or time to relapse.Data extraction Two independent raters selected studies and extracted data. Random effect models were used to estimate odds ratios for relapse, hazard ratios for time to relapse, and relapse prevalence per group. The effect of various categorical and continuous variables was explored with subgroup analyses and meta-regression analyses respectively. Bias was assessed using the Cochrane tool.Results The meta-analysis included 28 studies (n=5233) examining relapse with a maximum follow-up of one year. Across studies, risk of bias was considered low. Discontinuation increased the odds of relapse compared with continuing antidepressants (summary odds ratio 3.11, 95% confidence interval 2.48 to 3.89). Subgroup analyses and meta-regression analyses showed no statistical significance. Time to relapse (n=3002) was shorter when antidepressants were discontinued (summary hazard ratio 3.63, 2.58 to 5.10; n=11 studies). Summary relapse prevalences were 36.4% (30.8% to 42.1%; n=28 studies) for the placebo group and 16.4% (12.6% to 20.1%; n=28 studies) for the antidepressant group, but prevalence varied considerably across studies, most likely owing to differences in the length of follow-up. Dropout was higher in the placebo group (summary odds ratio 1.31, 1.06 to 1.63; n=27 studies).Conclusions Up to one year of follow-up, discontinuation of antidepressant treatment results in higher relapse rates among responders compared with treatment continuation. The lack of evidence after a one year period should not be interpreted as explicit advice to discontinue antidepressants after one year. Given the chronicity of anxiety disorders, treatment should be directed by long term considerations, including relapse prevalence, side effects, and patients' preferences.

Diagnostic instability of recurrence and the impact on recurrence rates in depressive and anxiety disorders.

BACKGROUND: Despite increasing evidence for the diagnostic instability between and within depressive and anxiety disorders, most studies report solely on the recurrence rates of the specific index disorders. Neglecting this evidence has an inherent risk of underestimating recurrence rates of depressive and anxiety disorders. This study investigates the impact of diagnostic instability of recurrence rates in depression and anxiety. METHODS: Data were derived from the Netherlands Study of Depression and Anxiety (NESDA). The sample of 656 participants had a panic disorder with or without agoraphobia, agoraphobia, social phobia, generalized anxiety disorder, major depressive disorder or dysthymia, and a subsequent remission. Recurrence rates of index disorders (diagnostically stable recurrence) and newly arisen anxiety or depressive disorders (diagnostically unstable recurrence), were calculated over a 4-year follow-up period. RESULTS: In anxiety disorders (n=281), the recurrence rate is more than doubled, from 23.8% with a stable recurrence, to 54.8%, when diagnostically unstable recurrences are included. In depressive disorders (N=173) the recurrence rate increases from 37.6% to 49.7%, and in comorbid anxiety and depressive disorders (N=202) the diagnostically unstable recurrences increase from 54.0% to 66.3%. LIMITATIONS: Attrition during follow up may have biased the results; remission was defined as absence of symptoms for 1 month; very short-term remission and recurrence patterns were not assessed. CONCLUSIONS: Diagnostically unstable recurrences have a significant impact on recurrence rates, with the greatest instability for anxiety disorders. When only diagnostically stable recurrences are assessed, recurrence rates are highly underrated and provide biased estimates of the true course of these disorders.

Leukemic stem cell frequency: a strong biomarker for clinical outcome in acute myeloid leukemia.

INTRODUCTION: Treatment failure in acute myeloid leukemia is probably caused by the presence of leukemia initiating cells, also referred to as leukemic stem cells, at diagnosis and their persistence after therapy. Specific identification of leukemia stem cells and their discrimination from normal hematopoietic stem cells would greatly contribute to risk stratification and could predict possible relapses. RESULTS: For identification of leukemic stem cells, we developed flow cytometric methods using leukemic stem cell associated markers and newly-defined (light scatter) aberrancies. The nature of the putative leukemic stem cells and normal hematopoietic stem cells, present in the same patient's bone marrow, was demonstrated in eight patients by the presence or absence of molecular aberrancies and/or leukemic engraftment in NOD-SCID IL-2Rγ-/- mice. At diagnosis (n=88), the frequency of the thus defined neoplastic part of CD34+CD38- putative stem cell compartment had a strong prognostic impact, while the neoplastic parts of the CD34+CD38+ and CD34- putative stem cell compartments had no prognostic impact at all. After different courses of therapy, higher percentages of neoplastic CD34+CD38- cells in complete remission strongly correlated with shorter patient survival (n=91). Moreover, combining neoplastic CD34+CD38- frequencies with frequencies of minimal residual disease cells (n=91), which reflect the total neoplastic burden, revealed four patient groups with different survival. CONCLUSION AND PERSPECTIVE: Discrimination between putative leukemia stem cells and normal hematopoietic stem cells in this large-scale study allowed to demonstrate the clinical importance of putative CD34+CD38- leukemia stem cells in AML. Moreover, it offers new opportunities for the development of therapies directed against leukemia stem cells, that would spare normal hematopoietic stem cells, and, moreover, enables in vivo and ex vivo screening for potential efficacy and toxicity of new therapies.