Patterns of psychotropic drug prescriptions and general practice consultations among community-dwelling older people with dementia during the first two years of the COVID-19 pandemic.

BACKGROUND: The COVID-19 pandemic and subsequent lockdown measures had serious implications for community-dwelling older people with dementia. While the short-term impacts of the pandemic on this population have been well studied, there is limited research on its long-term impacts. Quantifying the long-term impacts may provide insights into whether healthcare adaptations are needed after the acute phase of the pandemic to balance infection prevention measures with healthcare provision. This study aims to examine patterns of psychotropic drug prescriptions and general practice consultations in community-dwelling older people with dementia during the first two years of the pandemic. METHODS: We utilised routine electronic health records from three Dutch academic general practice research networks located in the North, East, and South, between 2019 and 2021. We (1) compared the weekly prescription rates of five groups of psychotropic drugs and two groups of tracer drugs, and weekly general practice consultation rates per 1000 participants, between the first two years of the pandemic and the pre-pandemic phase, (2) calculated changes in these rates during three lockdowns and two relaxation phases relative to the corresponding weeks in 2019, and (3) employed interrupted time series analyses for the prescription rates. Analyses were performed for each region separately. RESULTS: The study population sizes in the North, East, and South between 2019 and 2021 were 1726 to 1916, 93 to 117, and 904 to 960, respectively. Data from the East was excluded from the statistical analyses due to the limited sample size. During the first two years of the pandemic, the prescription rates of psychotropic drugs were either lower or similar to those in the pre-pandemic phase, with differences varying from -2.6‰ to -10.2‰. In contrast, consultation rates during the pandemic were higher than in the pre-pandemic phase, increasing by around 38‰. CONCLUSIONS: This study demonstrates a decrease in psychotropic drug prescriptions, but an increase in general practice consultations among community-dwelling older people with dementia during the first two years of the pandemic. However, reasons for the decrease in psychotropic drug prescriptions are unclear due to limited information on the presence of neuropsychiatric symptoms and the appropriateness of prescribing.

Accuracy of diagnostic tests for acute diverticulitis that are feasible in primary care: a systematic review and meta-analysis.

BACKGROUND: Recognition of acute diverticulitis is important to determine an adequate management strategy. Differentiating it from other gastrointestinal disorders is challenging as symptoms overlap. Clinical tests might assist the clinician with this diagnostic challenge. Previous reviews have focussed on prognostic questions and imaging examinations in secondary care. OBJECTIVE: To evaluate the diagnostic accuracy of clinical tests feasible in primary care for acute diverticulitis in suspected patients. METHOD: We have systematically searched multiple databases for diagnostic accuracy studies of tests feasible in primary care compared to a reference standard in suspected patients. Two reviewers independently selected studies, extracted data, and assessed study quality with the QUADAS-2 tool. We have meta-analysed the results in the case of more than four studies per index test. RESULTS: Seventeen studies were included, all studies were performed in secondary care (median prevalence 48%). Individual signs and symptoms showed a wide range in sensitivity (range 0.00-0.98) and specificity (range 0.08-1.00). Of the four laboratory tests evaluated, CRP >10 mg/l had the highest sensitivity (range 0.89-0.96) with specificity ranging from 0.28 to 0.61. Ultrasound had the highest pooled sensitivity and specificity of 0.92 (95% CI 0.86-0.96) and 0.94 (95% CI 0.88-0.97), respectively. CONCLUSION: None of the studies were performed in primary care. Individual signs and symptoms alone are insufficiently informative for acute diverticulitis diagnosis. CRP showed potential for ruling out and ultrasound had a high diagnostic accuracy. More research is needed about the diagnostic accuracy of these tests in primary care. PROSPERO REGISTRATION NUMBER: CRD42021230622.

Intergenerational impact of childhood trauma on hair cortisol concentrations in mothers and their young infants.

Background: Alterations in stress regulation and function of the hypothalamic-pituitary-adrenal (HPA) axis during infancy may be a risk factor for the development of psychopathology later in life. Maternal childhood trauma, depression, anxiety and stressful life events are individually associated with HPA axis dysregulation. Less is known about their interdependent influence on maternal and infant stress regulation in at risk populations. In a sample of mothers with a history of depressive-, and/or anxiety disorders and their infants we explored if a history of maternal childhood trauma, current depressive and anxiety symptomatology, and recent life events were associated with maternal and infant long-term cortisol levels three months postpartum. Methods: Data were available of 89 mothers and 49 infants. All mothers fulfilled criteria for a lifetime depressive or anxiety disorder. Diagnosis was established with a diagnostic interview. Current depressive symptomatology was assessed with the Edinburgh Postnatal Depression Scale (EPDS), current anxiety with the State-Trait Anxiety Inventory (STAI), maternal childhood trauma with the Childhood Trauma Questionnaire (CTQ) and recent life events with the Everyday Problem Checklist (EPC). Maternal and infant hair cortisol concentrations (HCC) were quantified with liquid chromatography with tandem mass spectrometry (LC-MS/MS) three months after birth. Total scores of the CTQ and subscales, EPDS, STAI, and EPC were regressed on maternal and infant HCC using regression analyses. Differences in HCC regarding trauma history were tested with t-tests. Potential confounders were identified and adjusted for. Results: In regression analyses, a positive curvilinear relationship was found between CTQ total score and maternal HCC (n = 83, B = 0.076, SE 0.033, p = .021), but not for current depression (n = 88, B = -0.001, SE 0.011, p = .931), current anxiety (n = 88, B = 0.002, SE 0.004, p = .650) or recent life events (n = 89, B = 0.018, SE 0.032, p = .568). Analyses were adjusted for confounders. A negative linear relationship was found between maternal CTQ score and infant HCC (n = 49, ß = -0.264, B = -0.006, SE 0.003, p = .052), but not for current maternal depression (n = 45, ß = -0.182, B = -0.011, SE 0.008, p = .164), current maternal anxiety (n = 45, ß = -0.209, B = -0.005, SE 0.003, p = .113) or recent life events (n = 46, ß = -0.128, B = -0.022, SE 0.023, p = .325). Analyses were adjusted for relevant infant hair characteristics. Specifically, maternal emotional and physical neglect were related to HCC in both mothers and infants. Conclusions: Results suggest that maternal childhood trauma is more prominent in altering maternal and infant long-term cortisol levels than perinatal depressive and anxiety symptomatology or recent life stressors in mothers with a history of depressive and/or anxiety disorders, and their infants. As infants of mothers with psychopathology are at increased risk for later psychiatric disease, future studies should investigate the interplay of possible risk factors for transgenerational transmission, intra-uterine programming of the HPA axis, including (epi-)genetic phenomena, of the HPA axis, and the influence of parenting impairment.

Recurrence of depression can be foreseen by monitoring mental states with statistical process control.

Detecting early signs of recurrence of psychopathology is key for prevention and treatment. Personalized risk assessment is especially relevant for formerly depressed patients, for whom recurrence is common. We aimed to examine whether recurrence of depression can be accurately foreseen by applying Exponentially Weighted Moving Average (EWMA) statistical process control charts to Ecological Momentary Assessment (EMA) data. Participants were formerly depressed patients (n = 41) in remission who (gradually) discontinued antidepressants. Participants completed five smartphone-based EMA questionnaires a day for 4 months. EWMA control charts were used to prospectively detect structural mean shifts in high and low arousal negative affect (NA), high and low arousal positive affect (PA), and repetitive negative thinking in each individual. A significant increase in repetitive negative thinking (worry, negative thoughts about the self) was the most sensitive early sign of recurrence: this was detected in 18 out of 22 patients (82%) before recurrence and in 8 out of 19 patients (42%) who stayed in remission. A significant increase in NA high arousal (stress, irritation, restlessness) was the most specific early sign of recurrence: this was detected in 10 out of 22 patients (45%) before recurrence and in 2 out of 19 patients (11%) who stayed in remission. These mean changes were detected at least a month before recurrence in the majority of the participants. The outcomes were robust across EWMA parameter choices, but not when using fewer observations per day. The findings demonstrate the value of monitoring EMA data with EWMA charts for detecting prodromal symptoms of depression in real-time. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Effects up to 20-Year Follow-Up of Preventive Cognitive Therapy in Adults Remitted from Recurrent Depression: The DELTA Study.

INTRODUCTION: Major depressive disorder (MDD) is common, and recurrence rates are high. Preventive Cognitive Therapy (PCT), has been shown to prolong time to recurrence and reduce risk of recurrence(s) over 2-10 years in patients with recurrent depression. OBJECTIVE: The aim of the study was to examine the effectiveness of PCT over 20 years on time to first recurrence, cumulative proportion of first recurrences, percentage of depression-free time, mean severity of recurrences, and the number of recurrences within a patient. METHODS: Adults remitted from recurrent MDD were randomized to PCT or Treatment As Usual (TAU). Clinical outcomes were assessed using the SCID over 20 years. We used Cox regression analyses, Kaplan-Meier analyses, ANOVA, and negative binomial regression and tested for interaction with the number of previous episodes. RESULTS: There was a significant interaction effect for number of previous episodes with treatment condition on time to first recurrence (Wald[1, n = 172] = 8.840, p = 0.003). For participants with more than 3 previous episodes, the mean time to recurrence was 4.8 years for PCT versus 1.6 years for TAU; the cumulative proportion of first recurrences was 87.5% for PCT and 100% for TAU. For participants with more than 3 previous episodes, exploratory analyses suggest that PCT had 53% less recurrences and percentage of depression-free time was significantly higher compared to TAU. There were no significant effects on mean severity. CONCLUSIONS: Up to 20 years, for MDD patients with more than 3 previous episodes, those who received PCT had significantly longer time to a first recurrence and lower recurrence risk and may have less recurrences and more depression-free time compared to TAU. This suggests long term protective effects of PCT up to 20-years.

Is suboptimal effort an issue? A systematic review on neuropsychological performance validity in major depressive disorder.

BACKGROUND: In Major Depressive Disorder (MDD), emotion- and motivation related symptoms may affect effort during neuropsychological testing. Performance Validity Tests (PVT's) are therefore essential, but are rarely mentioned in research on cognitive functioning in MDD. We aimed to assess the proportion of MDD patients with demonstrated valid performance and determine cognitive functioning in patients with valid performance. This is the first systematic review on neuropsychological performance validity in MDD. METHODS: Databases PubMed, PsycINFO, Embase, and Cochrane Library were searched for studies reporting on PVT results of adult MDD patients. We meta-analyzed the proportion of MDD patients with PVT scores indicative of valid performance. RESULTS: Seven studies with a total of 409 MDD patients fulfilled inclusion criteria. Six studies reported the exact proportion of patients with PVT scores indicative of valid performance, which ranged from 60 to 100 % with a proportion estimate of 94 %. Four studies reported on cognitive functioning in MDD patients with valid performance. Two out of these studies found memory impairment in a minority of MDD patients and two out of these studies found no cognitive impairment. LIMITATIONS: Small number of studies and small sample sizes. CONCLUSIONS: A surprisingly small number of studies reported on PVT in MDD. About 94 % of MDD patients in studies using PVT's had valid neuropsychological test performance. Concessive information regarding cognitive functioning in MDD patients with valid performance was lacking. Neuropsychological performance validity should be taken into account since this may alter conclusions regarding cognitive functioning.

Prediction model study focusing on eHealth in the management of urinary incontinence: the Personalised Advantage Index as a decision-making aid.

OBJECTIVE: To develop a prediction model and illustrate the practical potential of personalisation of treatment decisions between app-based treatment and care as usual for urinary incontinence (UI). DESIGN: A prediction model study using data from a pragmatic, randomised controlled, non-inferiority trial. SETTING: Dutch primary care from 2015, with social media included from 2017. Enrolment ended on July 2018. PARTICIPANTS: Adult women were eligible if they had ≥2 episodes of UI per week, access to mobile apps and wanted treatment. Of the 350 screened women, 262 were eligible and randomised to app-based treatment or care as usual; 195 (74%) attended follow-up. PREDICTORS: Literature review and expert opinion identified 13 candidate predictors, categorised into two groups: Prognostic factors (independent of treatment type), such as UI severity, postmenopausal state, vaginal births, general physical health status, pelvic floor muscle function and body mass index; and modifiers (dependent on treatment type), such as age, UI type and duration, impact on quality of life, previous physical therapy, recruitment method and educational level. MAIN OUTCOME MEASURE: Primary outcome was symptom severity after a 4-month follow-up period, measured by the International Consultation on Incontinence Questionnaire the Urinary Incontinence Short Form. Prognostic factors and modifiers were combined into a final prediction model. For each participant, we then predicted treatment outcomes and calculated a Personalised Advantage Index (PAI). RESULTS: Baseline UI severity (prognostic) and age, educational level and impact on quality of life (modifiers) independently affected treatment effect of eHealth. The mean PAI was 0.99±0.79 points, being of clinical relevance in 21% of individuals. Applying the PAI also significantly improved treatment outcomes at the group level. CONCLUSIONS: Personalising treatment choice can support treatment decision making between eHealth and care as usual through the practical application of prediction modelling. Concerning eHealth for UI, this could facilitate the choice between app-based treatment and care as usual. TRIAL REGISTRATION NUMBER: NL4948t.

Augmenting neurocognitive remediation therapy to Preventive Cognitive Therapy for partially remitted depressed patients: protocol of a pragmatic multicentre randomised controlled trial.

INTRODUCTION: Major depressive disorder (MDD) affects 163 million people globally every year. Individuals who experience subsyndromal depressive symptoms during remission (ie, partial remission of MDD) are especially at risk for a return to a depressive episode within an average of 4 months. Simultaneously, partial remission of MDD is associated with work and (psycho)social impairment and a lower quality of life. Brief psychological interventions such as preventive cognitive therapy (PCT) can reduce depressive symptoms or relapse for patients in partial remission, although achieving full remission with treatment is still a clinical challenge. Treatment might be more effective if cognitive functioning of patients is targeted as well since cognitive problems are the most persisting symptom in partial remission and predict poor treatment response and worse functioning. Studies show that cognitive functioning of patients with (remitted) MDD can be improved by online neurocognitive remediation therapy (oNCRT). Augmenting oNCRT to PCT might improve treatment effects for these patients by strengthening their cognitive functioning alongside a psychological intervention. METHODS AND ANALYSIS: This study will examine the effectiveness of augmenting oNCRT to PCT in a pragmatic national multicentre superiority randomised controlled trial. We will include 115 adults partially remitted from MDD with subsyndromal depressive symptoms defined as a Hamilton Depression Rating Scale score between 8 and 15. Participants will be randomly allocated to PCT with oNCRT, or PCT only. Primary outcome measure is the effect on depressive symptomatology over 1 year. Secondary outcomes include time to relapse, cognitive functioning, quality of life and healthcare costs. This first dual approach study of augmenting oNCRT to PCT might facilitate full remission in partially remitted individuals as well as prevent relapse over time. ETHICS AND DISSEMINATION: Ethical approval was obtained by Academic Medical Center, Amsterdam. Outcomes will be made publicly available. TRIAL REGISTRATION NUMBER: NL9582.

Pharmacological treatment for psychotic depression.

BACKGROUND: Evidence is limited regarding the most effective pharmacological treatment for psychotic depression: monotherapy with an antidepressant, monotherapy with an antipsychotic, another treatment (e.g. mifepristone), or combination of an antidepressant plus an antipsychotic. This is an update of a review first published in 2005 and last updated in 2015. OBJECTIVES: 1. To compare the clinical efficacy of pharmacological treatments for patients with an acute psychotic depression: antidepressant monotherapy, antipsychotic monotherapy, mifepristone monotherapy, and the combination of an antidepressant plus an antipsychotic versus placebo and/or each other. 2. To assess whether differences in response to treatment in the current episode are related to non-response to prior treatment. SEARCH METHODS: A search of the Cochrane Central Register of Controlled Trials (CENTRAL), in the Cochrane Library; the Cochrane Common Mental Disorders Controlled Trials Register (CCMDCTR); Ovid MEDLINE (1950-); Embase (1974-); and PsycINFO (1960-) was conducted on 21 February 2020. Reference lists of all included studies and related reviews were screened and key study authors contacted. SELECTION CRITERIA: All randomised controlled trials (RCTs) that included participants with acute major depression with psychotic features, as well as RCTs consisting of participants with acute major depression with or without psychotic features, that reported separately on the subgroup of participants with psychotic features. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed risk of bias in the included studies, according to criteria from the Cochrane Handbook for Systematic Reviews of Interventions. Data were entered into RevMan 5.1. We used intention-to-treat data. Primary outcomes were clinical response for efficacy and overall dropout rate for harm/tolerance. Secondary outcome were remission of depression, change from baseline severity score, quality of life, and dropout rate due to adverse effects. For dichotomous efficacy outcomes (i.e. response and overall dropout), risk ratios (RRs) with 95% confidence intervals (CIs) were calculated.  Regarding the primary outcome of harm, only overall dropout rates were available for all studies. If the study did not report any of the response criteria as defined above, remission as defined here could be used as an alternative. For continuously distributed outcomes, it was not possible to extract data from the RCTs.  MAIN RESULTS: The search identified 3947 abstracts, but only 12 RCTs with a total of 929 participants could be included in the review. Because of clinical heterogeneity, few meta-analyses were possible. The main outcome was reduction in severity (response) of depression, not of psychosis. For depression response, we found no evidence of a difference between antidepressant and placebo (RR 8.40, 95% CI 0.50 to 142.27; participants = 27, studies = 1; very low-certainty evidence) or between antipsychotic and placebo (RR 1.13, 95% CI 0.74 to 1.73; participants = 201, studies = 2; very low-certainty evidence). Furthermore, we found no evidence of a difference in overall dropouts with antidepressant (RR 1.24, 95% CI 0.34 to 4.51; participants = 27, studies = 1; very low-certainty evidence) or antipsychotic monotherapy (RR 0.79, 95% CI 0.57 to 1.08; participants = 201, studies = 2; very low-certainty evidence). No evidence suggests a difference in depression response (RR 2.09, 95% CI 0.64 to 6.82; participants = 36, studies = 1; very low-certainty evidence) or overall dropouts (RR 1.79, 95% CI 0.18 to 18.02; participants = 36, studies = 1; very low-certainty evidence) between antidepressant and antipsychotic. For depression response, low- to very low-certainty evidence suggests that the combination of an antidepressant plus an antipsychotic may be more effective than antipsychotic monotherapy (RR 1.83, 95% CI 1.40 to 2.38; participants = 447, studies = 4), more effective than antidepressant monotherapy (RR 1.42, 95% CI 1.11 to 1.80; participants = 245, studies = 5), and more effective than placebo (RR 1.86, 95% CI 1.23 to 2.82; participants = 148, studies = 2). Very low-certainty evidence suggests no difference in overall dropouts between the combination of an antidepressant plus an antipsychotic versus antipsychotic monotherapy (RR 0.79, 95% CI 0.63 to 1.01; participants = 447, studies = 4), antidepressant monotherapy (RR 0.91, 95% CI 0.55 to 1.50; participants = 245, studies = 5), or placebo alone (RR 0.75, 95% CI 0.48 to 1.18; participants = 148, studies = 2). No study measured change in depression severity from baseline, quality of life, or dropouts due to adverse events. We found no RCTs with mifepristone that fulfilled our inclusion criteria. Risk of bias is considerable: we noted differences between studies with regards to diagnosis, uncertainties around randomisation and allocation concealment, treatment interventions (pharmacological differences between various antidepressants and antipsychotics), and outcome criteria. AUTHORS' CONCLUSIONS: Psychotic depression is heavily under-studied, limiting confidence in the conclusions drawn. Some evidence indicates that combination therapy with an antidepressant plus an antipsychotic is more effective than either treatment alone or placebo. Evidence is limited for treatment with an antidepressant alone or with an antipsychotic alone. Evidence for efficacy of mifepristone is lacking.

Intrapartum synthetic oxytocin, behavioral and emotional problems in children, and the role of postnatal depressive symptoms, postnatal anxiety and mother-to-infant bonding: A Dutch prospective cohort study.

OBJECTIVE: To examine the association between intrapartum synthetic oxytocin and child behavioral and emotional problems and to assess if maternal depressive or anxious symptoms or mother-to-infant bonding play a mediating role in this association. DESIGN: Prospective cohort study. SETTING: Population-based Pregnancy Anxiety and Depression Study. PARTICIPANTS: Pregnant women in their first trimester of pregnancy visiting a total of 109 primary and nine secondary obstetric care centers in the Netherlands between 2010 and 2014 were invited to participate. Follow-up measures used for the present study were collected from May 2010 to January 2019. Women with multiple gestations and with a preterm birth were excluded. MEASUREMENTS: Intrapartum synthetic oxytocin exposure status was based on medical birth records and was defined as its administration (Yes/No), either for labour induction or augmentation. Child behavioral and emotional problems were measured with the Child Behavior Checklist at up to 60 months postpartum. Maternal depressive symptoms, anxiety and mother-to infant bonding were measured with the Edinburgh Postnatal Depression Scale, State Trait Anxiety Inventory and the Mother-to-Infant Bonding Scale from 6 months postpartum. We used multivariable linear regression models to estimate standardized beta coefficients and unique variance explained. FINDINGS: 1,528 women responded. In total 607 women received intrapartum synthetic oxytocin. Intrapartum synthetic oxytocin administration was not associated with child behavioral and emotional problems, mother-to-infant bonding nor with postnatal anxiety. Intrapartum synthetic oxytocin was however significantly but weakly associated with more postnatal depressive symptoms (ß=0.17, 95%CI of 0.03 to 0.30) explaining 0.6% of unique variance. Maternal postnatal depressive symptoms, postnatal anxiety symptoms and suboptimal mother-to-infant bonding were positively associated with child behavioral and emotional problems. KEY CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: We found no evidence that intrapartum synthetic oxytocin is associated with child behavioral and emotional problems, mother-to-infant bonding, or with postnatal anxiety symptoms. Because there was no association between intrapartum synthetic oxytocin and behavioral and emotional problems in children no mediation analysis was carried out. However, intrapartum synthetic oxytocin was positively but weakly associated with postnatal depressive symptoms. The clinical relevance of this finding is negligible in the general population, but unknown in a population with a high risk of depression.

Effectiveness of cognitive remediation in depression: a meta-analysis.

BACKGROUND: Preliminary evidence suggests beneficial effects of cognitive remediation in depression. An update of the current evidence is needed. The aim was to systematically assess the effectiveness of cognitive remediation in depression on three outcomes. METHODS: The meta-analysis was pre-registered on PROSPERO (CRD42019124316). PubMed, PsycINFO, Embase and Cochrane Library were searched on 2 February 2019 and 8 November 2020 for peer-reviewed published articles. We included randomized and non-randomized clinical trials comparing cognitive remediation to control conditions in adults with primary depression. Random-effects models were used to calculate Hedges' g, and moderators were assessed using mixed-effects subgroup analyses and meta-regression. Main outcome categories were post-treatment depressive symptomatology (DS), cognitive functioning (CF) and daily functioning (DF). RESULTS: We identified 5221 records and included 21 studies reporting on 24 comparisons, with 438 depressed patients receiving cognitive remediation and 540 patients in a control condition. We found a small effect on DS (g = 0.28, 95% CI 0.09-0.46, I2 40%), a medium effect on CF (g = 0.60, 95% CI 0.37-0.83, I2 44%) and a small effect on DF (g = 0.22, 95% CI 0.06-0.39, I2 3%). There were no significant effects at follow-up. Confounding bias analyses indicated possible overestimation of the DS and DF effects in the original studies. CONCLUSIONS: Cognitive remediation in depression improves CF in the short term. The effects on DS and DF may have been overestimated. Baseline depressive symptom severity should be considered when administering cognitive remediation.

Developing a clinical prediction rule for repeated consultations with functional somatic symptoms in primary care: a cohort study.

OBJECTIVES: Patients who present in primary care with chronic functional somatic symptoms (FSS) have reduced quality of life and increased health care costs. Recognising these early is a challenge. The aim is to develop and internally validate a clinical prediction rule for repeated consultations with FSS. DESIGN AND SETTING: Records from the longitudinal population-based ('Lifelines') cohort study were linked to electronic health records from general practitioners (GPs). PARTICIPANTS: We included patients consulting a GP with FSS within 1 year after baseline assessment in the Lifelines cohort. OUTCOME MEASURES: The outcome is repeated consultations with FSS, defined as ≥3 extra consultations for FSS within 1 year after the first consultation. Multivariable logistic regression, with bootstrapping for internal validation, was used to develop a risk prediction model from 14 literature-based predictors. Model discrimination, calibration and diagnostic accuracy were assessed. RESULTS: 18 810 participants were identified by database linkage, of whom 2650 consulted a GP with FSS and 297 (11%) had ≥3 extra consultations. In the final multivariable model, older age, female sex, lack of healthy activity, presence of generalised anxiety disorder and higher number of GP consultations in the last year predicted repeated consultations. Discrimination after internal validation was 0.64 with a calibration slope of 0.95. The positive predictive value of patients with high scores on the model was 0.37 (0.29-0.47). CONCLUSIONS: Several theoretically suggested predisposing and precipitating predictors, including neuroticism and stressful life events, surprisingly failed to contribute to our final model. Moreover, this model mostly included general predictors of increased risk of repeated consultations among patients with FSS. The model discrimination and positive predictive values were insufficient and preclude clinical implementation.

Explaining the Efficacy of an Internet-Based Behavioral Activation Intervention for Major Depression: A Mechanistic Study of a Randomized-Controlled Trial.

Background: Behavioral activation is an effective treatment for depression that is theorized to facilitate structured increases in enjoyable activities that increase opportunities for contact with positive reinforcement; to date, however, only few mechanistic studies focused on a standalone intervention. Method: Interventions using internet-based behavioral activation or psychoeducation were compared based on data from a randomized-controlled trial of 313 patients with major depressive disorder. Activation level and depression were measured fortnightly (baseline, Weeks 2, 4, 6, 8, 10), using the Patient Health Questionnaire-9 and the Behavioral Activation for Depression Scale-Short Form, respectively. Analysis was performed to determine if a change in activation level mediated treatment efficacy. Results: Latent growth modeling showed that internet-based behavioral activation treatment significantly reduced depressive symptoms from baseline to the end of treatment (standardized coefficient = -.13, p = .017) by increasing the rate of growth in the activation level (mediated effect estimate = -.17, 95% CI [-.27, -.07]. Results from mixed effects and simplex models showed that it took 4 weeks before mediation occurred (i.e., a significant change in activation that led to a reduction in depressive symptoms). Conclusion: Activation level likely mediated the therapeutic effect of behavioral activation on depression in our intervention. This finding may be of significant value to clinicians and depressed individuals who should anticipate a 4-week window before seeing a prominent change in activation level and a 6-week window before depressive symptomatology reduces. Future research must consolidate our findings on how behavioral activation works and when mediation occurs.

Tapering Antidepressants While Receiving Digital Preventive Cognitive Therapy During Pregnancy: An Experience Sampling Methodology Trial.

Background: Previous studies indicated that affect fluctuations, the use of antidepressant medication (ADM), as well as depression during pregnancy might have adverse effects on offspring outcomes. The aim of the current proof-of-principle study is to explore the effect of tapering ADM while receiving online preventive cognitive therapy (PCT) on pregnant women and the offspring as compared to pregnant women continuing ADM. Objectives: We sought to compare positive and negative affect fluctuations in pregnant women receiving online PCT while tapering ADM vs. pregnant women continuing ADM, and to investigate if affect fluctuations in early pregnancy were related to offspring birth weight. Method: An experience sampling methodology (ESM)-trial ran alongside a Dutch randomized controlled trial (RCT) and prospective observational cohort of women using ADM at the start of pregnancy. In the ESM-trial fluctuations of positive and negative affect were assessed in the first 8 weeks after inclusion. Recurrences of depression were assessed up to 12 weeks post-partum, and birth records were used to assess offspring birth weight. The RCT has been registered at the Netherlands Trial Register (NTR4694, https://www.trialregister.nl/trial/4551). Results: In total, 19 pregnant women using ADM at start of their pregnancy participated in the ESM-trial. There were no significant differences in positive and negative affect fluctuations, nor recurrence rates between women receiving PCT while tapering ADM vs. women continuing ADM. We found no association between affect fluctuations, pre-natal depressive symptoms, and birth weight (all p > 0.05). Conclusion: This explorative study showed that tapering ADM while receiving online PCT may protect pregnant women against recurrences of depression and affect fluctuations, without affecting birth weight. There is a high need for more controlled studies focusing on tapering ADM with (online) psychological interventions during pregnancy.

Effectiveness of a guided ACT-based self-help resilience training for depressive symptoms during pregnancy: Study protocol of a randomized controlled trial embedded in a prospective cohort.

BACKGROUND: During pregnancy, about 10 to 20% of women experience depressive symptoms. Subclinical depression increases the risk of peripartum depression, maternal neuro-endocrine dysregulations, and adverse birth and infant outcomes. Current treatments often comprise face-to-face psychological or pharmacological treatments that may be too intensive for women with subclinical depression leading to drop-out and moderate effectiveness. Therefore, easily accessible, resilience enhancing and less stigmatizing interventions are needed to prevent the development of clinical depression. This paper describes the protocol of a prospective cohort study with an embedded randomized controlled trial (RCT) that aims to improve mental resilience in a sample of pregnant women through a self-help program based on the principles of Acceptance and Commitment Therapy (ACT). Maternal and offspring correlates of the trajectories of peripartum depressive symptoms will also be studied. METHODS: Pregnant women (≥ 18 years) receiving care in Dutch midwifery practices will participate in a prospective cohort study (n ~ 3500). Between 12 and 18 weeks of pregnancy, all women will be screened for depression with the Edinburgh Postnatal Depression Scale (EPDS). Women with an EPDS score ≥ 11 will be evaluated with a structured clinical interview. Participants with subclinical depression (n = 290) will be randomized to a 9-week guided self-help ACT-training or to care as usual (CAU). Primary outcomes (depressive symptoms and resilience) and secondary outcomes (e.g. anxiety and PTSD, bonding, infant development) will be collected via online questionnaires at four prospective assessments around 20 weeks and 30 weeks gestation and at 6 weeks and 4 months postpartum. Maternal hair cortisol concentrations will be assessed in a subsample of women with a range of depressive symptoms (n = 300). The intervention's feasibility will be assessed through qualitative interviews in a subsample of participants (n = 20). DISCUSSION: This is the first study to assess the effectiveness of an easy to administer intervention strategy to prevent adverse mental health effects through enhancing resilience in pregnant women with antepartum depressive symptomatology. This longitudinal study will provide insights into trajectories of peripartum depressive symptoms in relation to resilience, maternal cortisol, psychological outcomes, and infant developmental milestones. TRIAL REGISTRATION: Netherlands Trial Register (NTR), NL7499 . Registered 5 February 2019.

Development of a risk classification model in early pregnancy to screen for suboptimal postnatal mother-to-infant bonding: A prospective cohort study.

BACKGROUND: Previous studies identified demographic, reproduction-related and psychosocial correlates of suboptimal mother-to-infant bonding. Their joint informative value was still unknown. This study aimed to develop a multivariable model to screen early in pregnancy for suboptimal postnatal mother-to-infant bonding and to transform it into a risk classification model. METHODS: Prospective cohort study conducted at 116 midwifery centers between 2010-2014. 634 women reported on the Mother-to-Infant Bonding questionnaire in 2015-2016. A broad range of determinants before 13 weeks of gestation were considered. Missing data were described, analyzed and imputed by multiple imputation. Multivariable logistic regression with backward elimination was used to develop a screening model. The explained variance, the Area Under the Curve of the final model were calculated and a Hosmer and Lemeshow test performed. Finally, we designed a risk classification model. RESULTS: The prevalence of suboptimal mother-to-infant bonding was 11%. The estimated probability of suboptimal mother-to-infant can be calculated: P(MIBS≥4) = 1/(1+exp(-(-4.391+(parity× 0.519)+(Adult attachment avoidance score× 0.040))). The explained variance was 14% and the Area Under the Curve was 0.750 (95%CI 0.690-0.809). The Hosmer and Lemeshow test had a p-value of 0.21. This resulted in a risk classification model. CONCLUSION: Parity and adult attachment avoidance were the strongest independent determinants. Higher parity and higher levels of adult attachment avoidance are associated with an increased risk of suboptimal mother-to-infant bonding. The model and risk classification model should be externally validated and optimized before use in daily practice. Future research should include an external validation study, a study into the additional value of non-included determinants and finally a study on the impact and feasibility of the screening model.

Effectiveness of digital psychological interventions for mental health problems in low-income and middle-income countries: a systematic review and meta-analysis.

BACKGROUND: The effectiveness of digital psychological interventions in low-income and middle-income countries (LMICs) remains unclear. We aimed to systematically investigate the available evidence for digital psychological interventions in reducing mental health problems in LMICs. METHODS: In this systematic review and meta-analysis, we searched PubMed, PsycINFO, Embase, and Cochrane databases for articles published in English from database inception to March 9, 2020. We included randomised controlled trials investigating digital psychological interventions in individuals with mental health problems in LMICs. We extracted data on demographics, inclusion and exclusion criteria, details of the intervention, including the setting, digital delivery method, control group conditions, number of sessions, therapeutic orientation (eg, cognitive therapy or behaviour therapy), presence or absence of guidance, and length of follow-up, and statistical information to calculate effect sizes. If a study reported insufficient data to calculate effect sizes, the corresponding authors were contacted to provide data that could be aggregated. We did random-effects meta-analyses, and calculated the standardised mean difference in scores of digital psychological interventions versus control conditions (Hedges'g). Quality of evidence was assessed by use of the Grading of Recommendations Assessment, Development, and Evaluation approach. The primary outcome was post-intervention mental health problems, as measured by self-reporting instruments or clinical interviews. This study is registered with PROSPERO, CRD42019137755. FINDINGS: We identified 22 eligible studies that were included in the meta-analysis. The included studies involved a total of 4104 participants (2351 who received a digital psychological intervention and 1753 who were in the control group), and mainly focused on young adults (mean age of the study population was 20-35 years) with depression or substance misuse. The results showed that digital psychological interventions are moderately effective when compared with control interventions (Hedges'g 0·60 [95% CI 0·45-0·75]; Hedges'g with treatment as usual subgroup for comparison 0·54 [0·35-0·73]). Heterogeneity between studies was substantial (I2=74% [95% CI 60-83]). There was no evidence of publication bias, and the quality of evidence according to the GRADE criteria was generally high. INTERPRETATION: Digital psychological interventions, which have been mostly studied in individuals with depression and substance misuse, are superior to control conditions, including usual care, and are moderately effective in LMICs. However, the considerable heterogeneity observed in our analysis highlights the need for more studies to be done, with standardised implementation of digital psychological intervention programmes to improve their reproducibility and efficiency. Digital psychological interventions should be considered for regions where usual care for mental health problems is minimal or absent. FUNDING: None. TRANSLATIONS: For the Persian, Chinese, Hindi, Portuguese, Bahasa, Turkish, Romanian, Spanish and Thai translations of the abstract see Supplementary Materials section.

Assessing risk of bias: a proposal for a unified framework for observational studies and randomized trials.

BACKGROUND: Evidence based medicine aims to integrate scientific evidence, clinical experience, and patient values and preferences. Individual health care professionals need to appraise the evidence from randomized trials and observational studies when guidelines are not yet available. To date, tools for assessment of bias and terminologies for bias are specific for each study design. Moreover, most tools appeal only to methodological knowledge to detect bias, not to subject matter knowledge, i.e. in-depth medical knowledge about a topic. We propose a unified framework that enables the coherent assessment of bias across designs. METHODS: Epidemiologists traditionally distinguish between three types of bias in observational studies: confounding, information bias, and selection bias. These biases result from a common cause, systematic error in the measurement or common effect of the intervention and outcome respectively. We applied this conceptual framework to randomized trials and show how it can be used to identify bias. The three sources of bias were illustrated with graphs that visually represent researchers' assumptions about the relationships between the investigated variables (causal diagrams). RESULTS: Critical appraisal of evidence started with the definition of the research question in terms of the population of interest, the compared interventions and the main outcome. Next, we used causal diagrams to illustrate how each source of bias can lead to over- or underestimated treatment effects. Then, we discussed how randomization, blinded outcome measurement and intention-to-treat analysis minimize bias in trials. Finally, we identified study aspects that can only be appraised with subject matter knowledge, irrespective of study design. CONCLUSIONS: The unified framework encompassed the three main sources of bias for the effect of an assigned intervention on an outcome. It facilitated the integration of methodological and subject matter knowledge in the assessment of bias. We hope that graphical diagrams will help clarify debate among professionals by reducing misunderstandings based on different terminology for bias.

Gender Differences in Developing Biomarker-Based Major Depressive Disorder Diagnostics.

The identification of biomarkers associated with major depressive disorder (MDD) holds great promise to develop an objective laboratory test. However, current biomarkers lack discriminative power due to the complex biological background, and not much is known about the influence of potential modifiers such as gender. We first performed a cross-sectional study on the discriminative power of biomarkers for MDD by investigating gender differences in biomarker levels. Out of 28 biomarkers, 21 biomarkers were significantly different between genders. Second, a novel statistical approach was applied to investigate the effect of gender on MDD disease classification using a panel of biomarkers. Eleven biomarkers were identified in men and eight in women, three of which were active in both genders. Gender stratification caused a (non-significant) increase of Area Under Curve (AUC) for men (AUC = 0.806) and women (AUC = 0.807) compared to non-stratification (AUC = 0.739). In conclusion, we have shown that there are differences in biomarker levels between men and women which may impact accurate disease classification of MDD when gender is not taken into account.