Dynamics of miRNA accumulation during C. elegans larval development.

Temporally and spatially controlled accumulation underlies the functions of microRNAs (miRNAs) in various developmental processes. In Caenorhabditis elegans, this is exemplified by the temporal patterning miRNAs lin-4 and let-7, but for most miRNAs, developmental expression patterns remain poorly resolved. Indeed, experimentally observed long half-lives may constrain possible dynamics. Here, we profile miRNA expression throughout C. elegans postembryonic development at high temporal resolution, which identifies dynamically expressed miRNAs. We use mathematical models to explore the underlying mechanisms. For let-7, we can explain, and experimentally confirm, a striking stepwise accumulation pattern through a combination of rhythmic transcription and stage-specific regulation of precursor processing by the RNA-binding protein LIN-28. By contrast, the dynamics of several other miRNAs cannot be explained by regulation of production rates alone. Specifically, we show that a combination of oscillatory transcription and rhythmic decay drive rhythmic accumulation of miR-235, orthologous to miR-92 in other animals. We demonstrate that decay of miR-235 and additional miRNAs depends on EBAX-1, previously implicated in target-directed miRNA degradation (TDMD). Taken together, our results provide insight into dynamic miRNA decay and establish a resource to studying both the developmental functions of, and the regulatory mechanisms acting on, miRNAs.

Molecular spikes: a gold standard for single-cell RNA counting.

Single-cell sequencing methods rely on molecule-counting strategies to account for amplification biases, yet no experimental strategy to evaluate counting performance exists. Here, we introduce molecular spikes-RNA spike-ins containing built-in unique molecular identifiers (UMIs) that we use to identify critical experimental and computational conditions for accurate RNA counting in single-cell RNA-sequencing (scRNA-seq). Using molecular spikes, we uncovered impaired RNA counting in methods that were not informative for cellular RNA abundances due to inflated UMI counts. We further leverage molecular spikes to improve estimates of total endogenous RNA amounts in cells, and introduce a strategy to correct experiments with impaired RNA counting. The molecular spikes and the accompanying R package UMIcountR ( https://github.com/cziegenhain/UMIcountR ) will improve the validation of new methods, better estimate and adjust for cellular mRNA amounts and enable more indepth characterization of RNA counting in scRNA-seq.

Behavioural Activation versus Treatment as Usual for Depressed Older Adults in Primary Care: A Pragmatic Cluster-Randomised Controlled Trial.

INTRODUCTION: Effective non-pharmacological treatment options for depression in older adults are lacking. OBJECTIVE: The effectiveness of behavioural activation (BA) by mental health nurses (MHNs) for depressed older adults in primary care compared with treatment as usual (TAU) was evaluated. METHODS: In this multicentre cluster-randomised controlled trial, 59 primary care centres (PCCs) were randomised to BA and TAU. Consenting older (≥65 years) adults (n = 161) with clinically relevant symptoms of depression (PHQ-9 ≥ 10) participated. Interventions were an 8-week individual MHN-led BA programme and unrestricted TAU in which general practitioners followed national guidelines. The primary outcome was self-reported depression (QIDS-SR16) at 9 weeks and 3, 6, 9, and 12-month follow-up. RESULTS: Data of 96 participants from 21 PCCs in BA and 65 participants from 16 PCCs in TAU, recruited between July 4, 2016, and September 21, 2020, were included in the intention-to-treat analyses. At post-treatment, BA participants reported significantly lower severity of depressive symptoms than TAU participants (QIDS-SR16 difference = -2.77, 95% CI = -4.19 to -1.35), p < 0.001; between-group effect size = 0.90; 95% CI = 0.42-1.38). This difference persisted up to the 3-month follow-up (QIDS-SR16 difference = -1.53, 95% CI = -2.81 to -0.26, p = 0.02; between-group effect size = 0.50; 95% CI = 0.07-0.92) but not up to the 12-month follow-up [QIDS-SR16 difference = -0.89 (-2.49 to 0.71)], p = 0.28; between-group effect size = 0.29 (95% CI = -0.82 to 0.24). CONCLUSIONS: BA led to a greater symptom reduction of depressive symptoms in older adults, compared to TAU in primary care, at post-treatment and 3-month follow-up, but not at 6- to 12-month follow-up.

Association Between Personality Traits and Functional Limitations in Older Adults with Affective Disorders: A Cross Sectional Study.

OBJECTIVES: Personality traits and affective disorders are both related to functional limitations. It is unknown whether personality traits have an additional effect on functioning in older adults with affective disorders. We studied the association between personality traits and functioning within this group. METHODS: We performed a cross-sectional study of 180 older patients referred to outpatient specialized geriatric mental health care centers with a depressive, anxiety and/or somatic symptom disorder according to DSM-criteria. We studied the association between the Big Five personality traits and functional limitations assessed with the WHO-DAS II, adjusting for potential confounders, including the severity of various affective disorders. RESULTS: The 180 patients (57.1% female, mean age 69.2 years) had an average WHO-DAS II score of 31.3 (SD 15.1). Lower scores on Conscientiousness were associated with more overall functional limitations (p = .001), particularly limitations in self-care (p = .001) and household activities (p = .001). Lower Extraversion scores were associated with more limitations in getting along with others (p = .001). CONCLUSIONS: Personality traits are related to functional limitations independent of the severity of affective disorders in older adults. CLINICAL IMPLICATIONS: Personality traits may be used as predictive factors for functioning in older adults with affective disorders.

Transcriptional bursts explain autosomal random monoallelic expression and affect allelic imbalance.

Transcriptional bursts render substantial biological noise in cellular transcriptomes. Here, we investigated the theoretical extent of allelic expression resulting from transcriptional bursting and how it compared to the amount biallelic, monoallelic and allele-biased expression observed in single-cell RNA-sequencing (scRNA-seq) data. We found that transcriptional bursting can explain the allelic expression patterns observed in single cells, including the frequent observations of autosomal monoallelic gene expression. Importantly, we identified that the burst frequency largely determined the fraction of cells with monoallelic expression, whereas the burst size had little effect on monoallelic observations. The high consistency between the bursting model predictions and scRNA-seq observations made it possible to assess the heterogeneity of a group of cells as their deviation in allelic observations from the expected. Finally, both burst frequency and size contributed to allelic imbalance observations and reinforced that studies of allelic imbalance can be confounded from the inherent noise in transcriptional bursting. Altogether, we demonstrate that allele-level transcriptional bursting renders widespread, although predictable, amounts of monoallelic and biallelic expression in single cells and cell populations.

Extensive oscillatory gene expression during C. elegans larval development.

Oscillations are a key to achieving dynamic behavior and thus occur in biological systems as diverse as the beating heart, defecating worms, and nascent somites. Here we report pervasive, large-amplitude, and phase-locked oscillations of gene expression in developing C. elegans larvae, caused by periodic transcription. Nearly one fifth of detectably expressed transcripts oscillate with an 8 hr period, and hundreds change >10-fold. Oscillations are important for molting but occur in all phases, implying additional functions. Ribosome profiling reveals that periodic mRNA accumulation causes rhythmic translation, potentially facilitating transient protein accumulation as well as coordinated production of stable, complex structures such as the cuticle. Finally, large-amplitude oscillations in RNA sampled from whole worms indicate robust synchronization of gene expression programs across cells and tissues, suggesting that these oscillations will be a powerful new model to study coordinated gene expression in an animal.

Impact of age-associated increase in 2'-O-methylation of miRNAs on aging and neurodegeneration in Drosophila.

MicroRNAs (miRNAs) are 20- to ∼24-nucleotide (nt) small RNAs that impact a variety of biological processes, from development to age-associated events. To study the role of miRNAs in aging, studies have profiled the levels of miRNAs with time. However, evidence suggests that miRNAs show heterogeneity in length and sequence in different biological contexts. Here, by examining the expression pattern of miRNAs by Northern blot analysis, we found that Drosophila miRNAs show distinct isoform pattern changes with age. Surprisingly, an increase of some miRNAs reflects increased 2'-O-methylation of select isoforms. Small RNA deep sequencing revealed a global increase of miRNAs loaded into Ago2, but not into Ago1, with age. Our data suggest increased loading of miRNAs into Ago2, but not Ago1, with age, indicating a mechanism for differential loading of miRNAs with age between Ago1 and Ago2. Mutations in Hen1 and Ago2, which lack 2'-O-methylation of miRNAs, result in accelerated neurodegeneration and shorter life span, suggesting a potential impact of the age-associated increase of 2'-O-methylation of small RNAs on age-associated processes. Our study highlights that miRNA 2'-O-methylation at the 3' end is modulated by differential partitioning of miRNAs between Ago1 and Ago2 with age and that this process, along with other functions of Ago2, might impact age-associated events in Drosophila.

Developmental function and state transitions of a gene expression oscillator in Caenorhabditis elegans.

Gene expression oscillators can structure biological events temporally and spatially. Different biological functions benefit from distinct oscillator properties. Thus, finite developmental processes rely on oscillators that start and stop at specific times, a poorly understood behavior. Here, we have characterized a massive gene expression oscillator comprising > 3,700 genes in Caenorhabditis elegans larvae. We report that oscillations initiate in embryos, arrest transiently after hatching and in response to perturbation, and cease in adults. Experimental observation of the transitions between oscillatory and non-oscillatory states at high temporal resolution reveals an oscillator operating near a Saddle Node on Invariant Cycle (SNIC) bifurcation. These findings constrain the architecture and mathematical models that can represent this oscillator. They also reveal that oscillator arrests occur reproducibly in a specific phase. Since we find oscillations to be coupled to developmental processes, including molting, this characteristic of SNIC bifurcations endows the oscillator with the potential to halt larval development at defined intervals, and thereby execute a developmental checkpoint function.

How Does Behavioural Activation Work? A Systematic Review of the Evidence on Potential Mediators.

INTRODUCTION: Behavioural activation is an effective treatment for depression, but little is known about its working mechanisms. Theoretically, its effect is thought to rely on an interplay between activation and environmental reward. OBJECTIVE: The present systematic review examines the mediators of behavioural activation for depression. METHODS: A systematic literature search without time restrictions in Medline, EMBASE, PsycINFO, The Cochrane Library, and CINAHL resulted in 14 relevant controlled and uncontrolled prospective treatment studies that also performed formal mediation analyses to investigate their working mechanisms. After categorising the mediators investigated, we systematically compared the studies' methodological quality and performed a narrative synthesis of the findings. RESULTS: Most studies focused on activation or environmental reward, with 21 different mediators being investigated using questionnaires that focused on psychological processes or beliefs. The evidence for both activation and environmental reward as mediators was weak. CONCLUSIONS: Non-significant results, poor methodological quality of some of the studies, and differences in questionnaires employed precluded any firm conclusions as to the significance of any of the mediators. Future research should exploit knowledge from fundamental research, such as reward motivation from neurobiology. Furthermore, the use of experience sampling methods and idiographic analyses in bigger samples is recommended to investigate potential causal pathways in individual patients.

Cognitive Remediation Therapy Does Not Enhance Treatment Effect in Obsessive-Compulsive Disorder and Anorexia Nervosa: A Randomized Controlled Trial.

BACKGROUND: Guideline-recommended therapies are moderately successful in the treatment of obsessive-compulsive disorder (OCD) and anorexia nervosa (AN), leaving room for improvement. Cognitive inflexibility, a common trait in both disorders, is likely to prevent patients from engaging in treatment and from fully benefiting from existing therapies. Cognitive remediation therapy (CRT) is a practical augmentation intervention aimed at ameliorating this impairing cognitive style prior to disorder-specific therapy. OBJECTIVE: To compare the effectiveness of CRT and a control treatment that was not aimed at enhancing flexibility, named specialized attention therapy (SAT), as add-ons to treatment as usual (TAU). METHODS: In a randomized controlled multicenter clinical trial, 71 adult patients with OCD and 61 with AN were randomized to ten twice-weekly sessions with either CRT or SAT, followed by TAU. Patients were evaluated at baseline, post-CRT/SAT, and after 6 and 12 months, with outcomes being quantified using the Yale-Brown Obsessive Compulsive Scale for OCD and the Eating Disorder Examination Questionnaire for AN. RESULTS: Across study groups, most importantly CRT+TAU was not superior to control treatment (SAT)+TAU in reducing OCD and AN pathology. Contrary to expectations, SAT+TAU may have been more effective than CRT+TAU in patients being treated for OCD. CONCLUSIONS: CRT did not enhance the effect of TAU for OCD and AN more than SAT. Unexpectedly, SAT, the control condition, may have had an augmentation effect on TAU in OCD patients. Although this latter finding may have been due to chance, the effect of SAT delivered as a pretreatment add-on intervention for adults with OCD and AN merits future efforts at replication.

Lower versus higher frequency of sessions in starting outpatient mental health care and the risk of a chronic course; a naturalistic cohort study.

BACKGROUND: An adequate frequency of treatment might be a prerequisite for a favorable outcome. Unfortunately, there is a diversity of factors that interfere with an adequate frequency of sessions. This occurs especially in the first phase of treatment, while the first phase seems vital for the rest of treatment. The aim of this naturalistic study was to explore the impact of the initial frequency of treatment sessions on treatment outcome in a diverse mental health care population. METHODS: Anonymized data were analyzed from 2,634 patients allocated for anxiety disorders, depressive disorders, and personality disorders to outpatient treatment programs in a large general mental health care facility. Patients' treatment outcome was routinely monitored with the Outcome Questionnaire-45 (OQ-45.2), every 12 weeks. Frequency of sessions was assessed for the first three months of treatment. Using Cox-proportional-hazard models, we explored the associations between initial frequency and improvement (reliable significant change) and recovery (reliable and clinically significant change). RESULTS: Improvement and recovery were associated with symptom severity and functional impairment at start of treatment, the year the treatment started, number of measurements, the treatment program (anxiety disorders, depressive disorders, and personality disorders) and receiving group therapy other than psychotherapy. In all diagnostic groups, both improvement and recovery were associated with a higher frequency of sessions during the first three months of treatment. For improvement, this effect diminished after three years in treatment; however, for recovery this association was sustained. CONCLUSIONS: In addition to severity at start of treatment and other predictors of outcome, a low frequency of initial treatment sessions might lead to a less favorable outcome and a more chronic course of the mental disorder. This association seems not to be limited to a specific diagnostic group, but was found in a large group of patients with common mental disorders (depression and anxiety disorders) and patients with a personality disorder. Despite organizational obstacles, more effort should be made to start treatment quickly by an effective frequency of session.

Study design of the Routine Outcome Monitoring for Geriatric Psychiatry & Science (ROM-GPS) project; a cohort study of older patients with affective disorders referred for specialised geriatric mental health care.

BACKGROUND: Affective disorders, encompassing depressive-, anxiety-, and somatic symptom disorders, are the most prevalent mental disorders in later life. Treatment protocols and guidelines largely rely on evidence from RCTs conducted in younger age samples and ignore comorbidity between these disorders. Moreover, studies in geriatric psychiatry are often limited to the "younger old" and rarely include the most frail. Therefore, the effectiveness of treatment in routine clinical care for older patients and impact of ageing characteristics is largely unknown. OBJECTIVE: The primary aim of the Routine Outcome Monitoring for Geriatric Psychiatry & Science (ROM-GPS) - project is to examine the impact of ageing characteristics on the effectiveness of treatment for affective disorders in specialised geriatric mental health care. METHODS: ROM-GPS is a two-stage, multicentre project. In stage one, all patients aged ≥60 years referred to participating outpatient clinics for specialised geriatric mental health care will be routinely screened with a semi-structured psychiatric interview, the Mini International Neuropsychiatric Interview and self-report symptom severity scales assessing depression, generalized anxiety, hypochondria, and alcohol use. Patients with a unipolar depressive, anxiety or somatic symptom disorder will be asked informed consent to participate in a second (research) stage to be extensively phenotyped at baseline and closely monitored during their first year of treatment with remission at one-year follow-up as the primary outcome parameter. In addition to a large test battery of potential confounders, specific attention is paid to cognitive functioning (including computerized tests with the Cogstate test battery as well as paper and pencil tests) and physical functioning (including multimorbidity, polypharmacy, and different frailty indicators). The study is designed as an ongoing project, enabling minor adaptations once a year (change of instruments). DISCUSSION: Although effectiveness studies using observational data can easily be biased, potential selection bias can be quantified and potentially corrected (e.g. by propensity scoring). Knowledge of age-related determinants of treatment effectiveness, may stimulate the development of new interventions. Moreover, studying late-life depressive, anxiety and somatic symptom disorders jointly enables data-driven studies for more optimal classification of these disorders in later life. TRIAL REGISTRATION: Dutch Trial Register: NL6704 ( www.trialregister.nl ). Retrospectively registered on 2017-12-05.

Chronic obsessive-compulsive disorder: prognostic factors.

BACKGROUND: The course of illness in obsessive-compulsive disorder (OCD) varies significantly between patients. Little is known about factors predicting a chronic course of illness. The aim of this study is to identify factors involved in inducing and in maintaining chronicity in OCD. METHODS: The present study is embedded within the Netherlands Obsessive Compulsive Disorder Association (NOCDA) study, an ongoing multicenter naturalistic cohort study designed to identify predictors of long-term course and outcome in OCD. For this study, 270 subjects with a current diagnosis of OCD were included. Chronicity status at 2-year follow-up was regressed on a selection of baseline predictors related to OCD, to comorbidity and to stress and support. RESULTS: Psychotrauma [odds ratio (OR) 1.98, confidence interval (CI) 1.22-3.22, p = 0.006], recent negative life events (OR 1.42, CI 1.01-2.01, p = 0.043), and presence of a partner (OR 0.28, CI 0.09-0.85, p = 0.025) influenced the risk of becoming chronic. Longer illness duration (OR 1.46, CI 1.08-1.96, p = 0.013) and higher illness severity (OR 1.09, CI 1.03-1.16, p = 0.003) increased the risk of remaining chronic. CONCLUSIONS: External influences increase the risk of becoming chronic, whereas the factors involved in maintaining chronicity are illness-related. As the latter are potentially difficult to modify, treatment should be devoted to prevent chronicity from occurring in the first place. Therapeutic strategies aimed at alleviating stress and at boosting social support might aid in achieving this goal.

The microRNA miR-34 modulates ageing and neurodegeneration in Drosophila.

Human neurodegenerative diseases have the temporal hallmark of afflicting the elderly population. Ageing is one of the most prominent factors to influence disease onset and progression, yet little is known about the molecular pathways that connect these processes. To understand this connection it is necessary to identify the pathways that functionally integrate ageing, chronic maintenance of the brain and modulation of neurodegenerative disease. MicroRNAs (miRNA) are emerging as critical factors in gene regulation during development; however, their role in adult-onset, age-associated processes is only beginning to be revealed. Here we report that the conserved miRNA miR-34 regulates age-associated events and long-term brain integrity in Drosophila, providing a molecular link between ageing and neurodegeneration. Fly mir-34 expression exhibits adult-onset, brain-enriched and age-modulated characteristics. Whereas mir-34 loss triggers a gene profile of accelerated brain ageing, late-onset brain degeneration and a catastrophic decline in survival, mir-34 upregulation extends median lifespan and mitigates neurodegeneration induced by human pathogenic polyglutamine disease protein. Some of the age-associated effects of miR-34 require adult-onset translational repression of Eip74EF, an essential ETS domain transcription factor involved in steroid hormone pathways. Our studies indicate that miRNA-dependent pathways may have an impact on adult-onset, age-associated events by silencing developmental genes that later have a deleterious influence on adult life cycle and disease, and highlight fly miR-34 as a key miRNA with a role in this process.

Intensive prolonged exposure treatment for adolescent complex posttraumatic stress disorder: a single-trial design.

BACKGROUND: The current study evaluated the effectiveness and safety of intensive prolonged exposure (PE) targeting adolescent patients with complex posttraumatic stress disorder (PTSD) and comorbid disorders following multiple interpersonal trauma. METHODS: Ten adolescents meeting full diagnostic criteria for PTSD were recruited from a specialized outpatient mental health clinic and offered a standardized intensive PE. The intensive PE consisted of three daily 90-min exposure sessions delivered on five consecutive weekdays, followed by 3 weekly 90-min booster sessions. In a single-trial design, the participants were randomly allocated to one of five baseline lengths (4-8 weeks) before starting the intensive PE. Before, during, and after intensive PE completion, self-reported PTSD symptom severity was assessed weekly as a primary outcome (a total of 21 measurements). Furthermore, clinician-administered PTSD diagnostic status and symptom severity (primary outcome), as well as self-reported comorbid symptoms (secondary outcomes), were assessed at four single time points (baseline-to-6-month follow-up). RESULTS: Time-series analyses showed that self-reported PTSD symptom severity significantly declined following treatment (p = .002). Pre-postgroup analyses demonstrated significant reductions of clinician-administered PTSD symptom severity and self-reported comorbidity that persisted during the 3- and 6-month follow-ups (all ps < .05), where 80% of adolescents had reached diagnostic remission of PTSD. There was neither treatment dropout nor any adverse events. CONCLUSIONS: The results of this first proof of concept trial suggest that intensive PE can be effective and safe in an adolescent population with complex PTSD, although the gains achieved need to be confirmed in a randomized controlled trial.

Behavioural activation by mental health nurses for late-life depression in primary care: a randomized controlled trial.

BACKGROUND: Depressive symptoms are common in older adults. The effectiveness of pharmacological treatments and the availability of psychological treatments in primary care are limited. A behavioural approach to depression treatment might be beneficial to many older adults but such care is still largely unavailable. Behavioural Activation (BA) protocols are less complicated and more easy to train than other psychological therapies, making them very suitable for delivery by less specialised therapists. The recent introduction of the mental health nurse in primary care centres in the Netherlands has created major opportunities for improving the accessibility of psychological treatments for late-life depression in primary care. BA may thus address the needs of older patients while improving treatment outcome and lowering costs.The primary objective of this study is to compare the effectiveness and cost-effectiveness of BA in comparison with treatment as usual (TAU) for late-life depression in Dutch primary care. A secondary goal is to explore several potential mechanisms of change, as well as predictors and moderators of treatment outcome of BA for late-life depression. METHODS/DESIGN: Cluster-randomised controlled multicentre trial with two parallel groups: a) behavioural activation, and b) treatment as usual, conducted in primary care centres with a follow-up of 52 weeks. The main inclusion criterion is a PHQ-9 score > 9. Patients are excluded from the trial in case of severe mental illness that requires specialized treatment, high suicide risk, drug and/or alcohol abuse, prior psychotherapy, change in dosage or type of prescribed antidepressants in the previous 12 weeks, or moderate to severe cognitive impairment. The intervention consists of 8 weekly 30-min BA sessions delivered by a trained mental health nurse. DISCUSSION: We expect BA to be an effective and cost-effective treatment for late-life depression compared to TAU. BA delivered by mental health nurses could increase the availability and accessibility of non-pharmacological treatments for late-life depression in primary care. TRIAL REGISTRATION: This study is retrospectively registered in the Dutch Clinical Trial Register NTR6013 on August 25th 2016.

Symptom Reduction Without Remoralization: A Randomized, Waiting-List Controlled Study Aimed at Separating Two Beneficial Psychotherapy Outcome Effects.

OBJECTIVE: Treatment effects in psychotherapy outcome research are generally based on the reduction of symptoms. Standard inclusion of other beneficial treatment effects such as remoralization (increase of hope, self-efficacy, well-being) might lead to more elaborate findings in the field of psychotherapy. On the other hand, it is also possible that symptom reduction and remoralization always go hand in hand in the experience of patients. The present study sought to experimentally test this assumption. METHOD: A total of 78 patients suffering from panic disorder were randomly assigned to brief remoralization treatment, brief exposure treatment, or waiting list (WL). RESULTS: Both treatments increased remoralization and both reduced symptoms of panic disorder as compared to WL. CONCLUSION: It is unlikely that patients experience remoralization without symptom reduction or symptom reduction without remoralization. These findings do not favor the assumption that conclusions within psychotherapy outcome research are flawed because of its heavy reliance on measurements of symptom reduction.

Cognitive remediation therapy (CRT) as a treatment enhancer of eating disorders and obsessive compulsive disorders: study protocol for a randomized controlled trial.

BACKGROUND: Anorexia nervosa (AN) and Obsessive Compulsive Disorder (OCD) are among the most incapacitating and costly of mental disorders. Cognitive Behaviour Therapy (CBT), medication, and combination regimens, to which in AN personalised guidance on weight control is added, are moderately successful, leaving room for more effective treatment algorithms. An underlying deficit which the two disorders share is cognitive inflexibility, a trait that is likely to impede treatment engagement and reduce patients' ability to benefit from treatment. Cognitive remediation therapy (CRT) is an easy-to-use intervention aimed at reducing cognitive inflexibility and thereby enhancing treatment outcome, which we aim to test in a controled study. METHODS: In a randomized-controlled multicenter clinical trial 64 adult patients with AN and 64 with OCD are randomized to 10 bi-weekly sessions with either CRT or a control condition, after which Treatment As Usual (TAU) is started. All patients are evaluated during single-blind assessments at baseline, post-CRT/control intervention, and after 6 months. Indices of treatment effect are disorder-specific symptom severity, quality of life, and cost-effectivity. Also, moderators and mediators of treatment effects will be studied. DISCUSSION: To our knowledge, this is the first randomized controlled trial using an control condition evaluating the efficacy and effectiveness of CRT as a treatment enhancer preceding TAU for AN, and the first study to investigate CRT in OCD, moreover taking cost-effectiveness of CRT in AN and OCD into account. TRIAL REGISTRATION: The Netherlands Trial Register NTR3865 . Registered 20 february 2013.

Cognitive-behavioral therapy for panic disorder with agoraphobia in older people: a comparison with younger patients.

BACKGROUND: Older adults with panic disorder and agoraphobia (PDA) are underdiagnosed and undertreated, while studies of cognitive-behavioral therapy (CBT) are lacking. This study compares the effectiveness of CBT for PDA in younger and older adults. METHODS: A total of 172 patients with PDA (DSM-IV) received manualized CBT. Primary outcome measures were avoidance behavior (Mobility Inventory Avoidance scale) and agoraphobic cognitions (Agoraphobic Cognitions Questionnaire), with values of the younger (18-60 years) and older (≥ 60 years) patients being compared using mixed linear models adjusted for baseline inequalities, and predictive effects of chronological age, age at PDA onset and duration of illness (DOI) being examined using multiple linear regressions. RESULTS: Attrition rates were 2/31 (6%) for the over-60s and 31/141 (22%) for the under-60s group (χ(2) = 3.43, df = 1, P = .06). Patients in both age groups improved on all outcome measures with moderate-to-large effect sizes. Avoidance behavior had improved significantly more in the 60+ group (F = 4.52, df = 1,134, P = .035), with agoraphobic cognitions showing no age-related differences. Baseline severity of agoraphobic avoidance and agoraphobic cognitions were the most salient predictors of outcome (range standardized betas 0.59 through 0.76, all P-values < .001). Apart from a superior reduction of agoraphobic avoidance in the 60+ participants (ß = -0.30, P = .037), chronological age was not related to outcome, while in the older patients higher chronological age, late-onset type and short DOI were linked to superior improvement of agoraphobic avoidance. CONCLUSIONS: CBT appears feasible for 60+ PDA-patients, yielding outcomes that are similar and sometimes even superior to those obtained in younger patients.