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Introduction: Cognitive reactivity to sad mood refers to the degree to which a mild dysphoric state reactivates dysfunctional cognitions, or negative thinking patterns, which has been found to be a vulnerability marker of depression. Over a two year period, Kruijt et al. (2013) found that only cognitive reactivity, including baseline symptoms and negative life events, predicted first onset of depression in a multivariate model. Objectives: The current study extends the findings of Kruijt et al. (2013) by evaluating the predictive association of cognitive reactivity on depression onset and depressive relapse over a follow-up period of nine years. Methods: Data were collected during a nine-year period in a prospective cohort study for depression and anxiety in the Netherlands. At baseline, 2981 participants recruited. We analyze data using Cox hazards regression models and ROC curves using subsamples of never-depressed and remitted-depressed participants. Results: Replicating the findings of Kruijt et al (2013), cognitive reactivity is expected to be significantly associated with depression incidence. Moreover, higher CR scores at baseline are expected to predict depressive relapse over a nine-year period, even when subclinical symptoms and other relevant predictive factors are controlled for. Conclusions: Our findings strengthen the support for the theory that depression-related cognitions precede the first onset of depression and predispose individuals to a poor depression prognosis, namely depression relapse. These findings emphasize the clinical importance of targeting dysfunctional cognitions in preventing the occurrence, or recurrence, of depression. [ABSTRACT FROM AUTHOR]

Background: Prolonged exposure (PE) is an effective treatment for post-traumatic stress disorder (PTSD). Objective: This study aimed to analyse the cost-effectiveness of three exposure-based treatments in patients with childhood abuse-related PTSD. Method: A net-benefit analysis was conducted alongside a pragmatic randomized controlled trial with participants ( N  = 149) randomized to three conditions: PE ( n =  48), intensified PE (i-PE, n  = 51), and phase-based PE [Skills Training in Affective and Interpersonal Regulation (STAIR) + PE, n  = 50]. Assessments took place at baseline (T0), post-treatment (T3), 6 month follow-up (T4), and 12 month follow-up (T5). Costs stemming from healthcare utilization and productivity losses were estimated using the Trimbos/iMTA questionnaire for Costs associated with Psychiatric Illness. Quality-adjusted life-years (QALYs) were based on the 5-level EuroQoL 5 Dimensions (EQ-5D-5L) using the Dutch tariff. Missing values of costs and utilities were multiply imputed. To compare i-PE to PE and STAIR + PE to PE, pair-wise unequal-variance t -tests were conducted. Net-benefit analysis was used to relate costs to QALYs and to draw acceptability curves. Results: Intervention costs did not differ across the three treatment conditions. Total medical costs, productivity losses, total societal costs, and EQ-5D-5L-based QALYs did not differ between treatment conditions either (all p  > .10). At the relevant €50,000/QALY threshold, the probability of one treatment being more cost-effective than another was 32%, 28%, and 40% for PE, i-PE, and STAIR-PE, respectively. Conclusion: Three equally effective treatments were compared and no differences in cost-effectiveness between treatments were found. Therefore, we advocate the implementation and adoption of any of the treatments and endorse shared decision making.

Background : It is unclear whether the evidence-based treatments for PTSD are as effective in patients with CA-PTSD. Objective : We aimed to investigate the effectiveness of three variants of prolonged exposure therapy. Method : We recruited adults with CA-PTSD. Participants were randomly assigned to Prolonged Exposure (PE; 16 sessions in 16 weeks), intensified Prolonged Exposure (iPE; 12 sessions in 4 weeks followed by 2 booster sessions) or a phase-based treatment, in which 8 sessions of PE were preceded by 8 sessions of Skills Training in Affective and Interpersonal Regulation (STAIR+PE; 16 sessions in 16 weeks). Assessments took place in week 0 (baseline), week 4, week 8, week 16 (post-treatment) and at a 6-and 12-month follow-up. The primary outcome was clinician-rated PTSD symptom severity. Results : We randomly assigned 149 patients to PE (48), iPE (51) or STAIR+PE (50). All treatments resulted in large improvements in clinician assessed and self-reported PTSD symptoms from baseline to 1-year follow-up (Cohen's d > 1.6), with no significant differences among treatments. iPE led to faster initial symptom reduction than PE for self-report PTSD symptoms ( t 135  = -2.85, p = .005, d = .49) but not clinician-assessed symptoms (t 135  = -1.65, p = .10) and faster initial symptom reduction than STAIR+PE for self-reported ( t 135  = -4.11, p < .001, d = .71) and clinician-assessed symptoms ( t 135  = -2.77, p = .006, Cohen's d = .48) STAIR+PE did not result in significantly more improvement from baseline to 1-year follow-up on the secondary outcome emotion regulation, interpersonal problems and self-esteem compared to PE and iPE. Dropout rates did not differ significantly between conditions. Conclusions : Variants of exposure therapy are tolerated well and lead to large improvements in patients with CA-PTSD. Intensifying treatment may lead to faster improvement but not to overall better outcomes. The trial is registered at the clinical trial registry, number NCT03194113, https://clinicaltrials.gov/ct2/show/NCT03194113., Competing Interests: Dr. van Minnen reports personal fees from Royalties and fees, outside the submitted work; Dr. Cloitre reports personal fees from Royalites and fees British Psychological Society San Francisco University Department of Psychiatry during the conduct of the study; Drs. Oprel, Drs. Hoeboer, Dr. Schoorl, Dr. van der Does, Drs. Wigard and Dr. de Kleine report no financial relationships with commercial interests., (© 2021 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.)

Background: The recommendations of experts who write review articles are a critical determinant of the adaptation of new treatments by clinicians. Several types of reviews exist (narrative, systematic, meta-analytic), and some of these are more vulnerable to researcher bias than others. Recently, the interest in nutritional interventions in psychiatry has increased and many experts, who are often active researchers on this topic, have come to strong conclusions about the benefits of a healthy diet on depression. In a young and active field of study, we aimed to investigate whether the strength of an author's conclusion is associated with the type of review article they wrote., Methods: Systematic searches were performed in PubMed, Web of Science, Cochrane Database of Systematic Reviews, and Google Scholar for narrative reviews and systematic reviews with and without meta-analyses on the effects of diet on depression (final search date: May 30th, 2020). Conclusions were extracted from the abstract and discussion section and rated as strong, moderate, or weak by independent raters who were blind to study type. A benchmark on legitimate conclusion strength was based on a GRADE assessment of the highest level of evidence. This systematic review was registered with PROSPERO, number CRD42020141372., Findings: 24 narrative reviews, 12 systematic reviews, and 14 meta-analyses were included. In the abstract, 33% of narrative reviews and 8% of systematic reviews came to strong conclusions, whereas no meta-analysis did. Narrative reviews were 8.94 (95% CI: 2.17, 36.84) times more likely to report stronger conclusions in the abstract than systematic reviews with and without meta-analyses. These findings were similar for conclusions in the discussion section. Narrative reviews used 45.6% fewer input studies and were more likely to be written by authors with potential conflicts of interest. A study limitation is the subjective nature of the conclusion classification system despite high inter-rater agreements and its confirmation outside of the review team., Conclusions: We have shown that narrative reviews come to stronger conclusions about the benefits of a healthy diet on depression despite inconclusive evidence. This finding empirically underscores the importance of a systematic method for summarizing the evidence of a field of study. Journal editors may want to reconsider publishing narrative reviews before meta-analytic reviews are available., Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: Without relevance to this work, P. Molero reports to have received research grants from the Ministry of Education (Spain), the Government of Navarra (Spain), the Spanish Foundation of Psychiatry and Mental Health and AstraZeneca; he is a clinical consultant for MedAvanteProPhase and has received lecture honoraria from or has been a consultant for AB-Biotics, Janssen, Novumed, Roland Berger, and Scienta. This does not alter our adherence to PLOS ONE policies on sharing data and materials. The other authors declare no competing interests.

Stress can impair cognitive performance, as commonly observed in cognitive performance anxiety (CPA; e.g., test anxiety). Cognitive theories indicate that stress impairs performance by increasing attention to negative thoughts, a phenomenon also known as threat-interference. These theories are mainly supported by findings related to self-report measures of threat-interference or trait anxiety. Our main aim was to test, for the first time in a single study, the hypotheses that acute CPA-related stress negatively affects both working memory (WM) performance and objectively assessed threat-interference during performance. In addition, we aimed to assess the validity of a new stress-induction procedure that was developed to induce acute CPA. Eighty-six females were randomly assigned to a CPA-related stress group (n = 45) or a control group. WM performance and threat-interference were assessed with an n-back task (2-back and 3-back memory loads), using CPA-related words as distracters. The stress group showed higher state anxiety and slower WM performance. Both effects were moderated by trait CPA: the effects were stronger for individuals with higher trait CPA. Finally, trait CPA moderated the effect of stress on threat-interference during higher cognitive load: individuals with higher trait CPA in the stress group showed higher threat-interference. We conclude that acute CPA increases threat-interference and impairs WM performance, especially in vulnerable individuals. The role of threat-interference, cognitive load, and trait anxiety should be taken into account in future research. Finally, our method (combining our stressor and modified n-back task) is effective for studying stress-cognition interactions in CPA., Competing Interests: The authors have declared that no competing interests exist.

Transcutaneous stimulation of the auricular branch of the vagus nerve (tVNS) may accelerate fear extinction in healthy humans. Here, we aimed to investigate this hypothesis in healthy young participants in a prepared learning paradigm, using spider pictures as conditioned stimuli. After a fear conditioning phase, participants were randomly allocated to receive tVNS (final N = 42) or sham stimulation (final N = 43) during an extinction phase. Conditioned fear was assessed using US expectancy ratings, skin conductance and fear potentiated startle responses. After successful fear acquisition, participants in both groups showed a reduction of fear over the course of the extinction phase. There were no between-group differences in extinction rates for physiological indices of fear. Contrary to previous findings, participants in the tVNS condition also did not show accelerated declarative extinction learning. Participants in the tVNS condition did have lower initial US expectancy ratings for the CS- trials than those who received sham stimulation, which may indicate an enhanced processing of safety cues due to tVNS. In conclusion, the expected accelerated extinction due to tVNS was not observed. The results from this study call for more research on the optimal tVNS stimulation intensity settings.

Background: Severe leptospirosis is frequently complicated by a hemorrhagic diathesis, of which the pathogenesis is still largely unknown. Thrombocytopenia is common, but often not to the degree that spontaneous bleeding is expected. We hypothesized that the hemorrhagic complications are not only related to thrombocytopenia, but also to platelet dysfunction, and that increased binding of von Willebrand factor (VWF) to platelets is involved in both platelet dysfunction and increased platelet clearance., Methodology/principal Findings: A prospective study was carried out in Semarang, Indonesia, enrolling 33 hospitalized patients with probable leptospirosis, of whom 15 developed clinical bleeding, and 25 healthy controls. Platelet activation and reactivity were determined using flow cytometry by measuring the expression of P-selectin and activation of the αIIbβ3 integrin by the binding of fibrinogen in unstimulated samples and after ex vivo stimulation by the platelet agonists adenosine-diphosphate (ADP) and thrombin-receptor activating peptide (TRAP). Platelet-VWF binding, before and after VWF stimulation by ristocetin, as well as plasma levels of VWF, active VWF, the VWF-inactivating enzyme ADAMTS13, thrombin-antithrombin complexes (TAT) and P-selectin were also measured. Bleeding complications were graded using the WHO bleeding scale. Our study revealed that platelet activation, with a secondary platelet dysfunction, is a feature of patients with probable leptospirosis, especially in those with bleeding manifestations. There was a significant inverse correlation of bleeding score with TRAP-stimulated P-selectin and platelet-fibrinogen binding (R = -0.72, P = 0.003 and R = -0.66, P = 0.01, respectively) but not with platelet count. Patients with bleeding also had a significantly higher platelet-VWF binding. Platelet counts were inversely correlated with platelet-VWF binding (R = -0.74; P = 0.0009. There were no correlations between platelet-VWF binding and the degree of platelet dysfunction, suggesting that increased platelet-VWF binding does not directly interfere with the platelet αIIbβ3 signaling pathway in patients with probable leptospirosis., Conclusion/significance: Platelet dysfunction is common in probable leptospirosis patients with manifest bleeding. Increased VWF-platelet binding may contribute to the activation and clearance of platelets.

Experimental manipulation of serotonin (5-HT) availability has been shown to modulate social behavior. For instance, serotonin depletion increased the rejection rates of unfair offers in the ultimatum game (UG), whereas a single dose of the serotonin reuptake inhibitor (citalopram) decreased rejection rates. These effects were observed immediately after the manipulation. The aim of this study was to investigate the effect of prolonged tryptophan (TRP) supplementation on UG performance in healthy individuals. A randomized double-blind placebo (PLC)-controlled design was used. Healthy volunteers (N = 47) completed the UG before and after a 6-day intervention of TRP (2.8 g/day) or PLC. Impulsivity was measured with a Go-Stop task. The overall analyses showed that TRP supplementation had no significant effect on UG scores, but the direction of the effect was opposite from expectations. Because repeated performance of the UG may lead to unwanted learning effects or strategical changes, additional analyses were conducted in which participants (N = 7) who accepted all offers on the second measurement were excluded. These analyses revealed that the TRP-group rejected very unfair offers more often than the PLC group. The groups did not differ on impulsivity. Increasing serotonin through TRP supplements increased the rejection of very unfair offers. The direction of our findings is inconsistent with earlier studies that showed that increasing 5-HT availability results in less rejection of unfair offers. The current findings thus importantly suggest that effects of acute vs. prolonged enhancement of 5-HT availability may differ. Also, the outcomes show that the UG is a complex task and participants' decisions may depend on context, e.g., prior experience with the task.

Introduction: Celiac disease (CD) is associated with an increased risk of major depressive disorder, possibly due to deficiencies in micronutrients in the gluten-free diet. We aimed to investigate whether essential amino acids (i.e., the precursors of serotonin, dopamine and other neurotransmitters) are depleted in the diet and serum of CD patients with major depressive disorder., Methods: In a cross-sectional study we assessed dietary intake of amino acids and serum levels of amino acids, in 77 CD patients on a gluten-free diet and in 33 healthy controls. Major depressive disorder was assessed with structured interviews (using the Mini International Neuropsychiatric Interview Plus). Dietary intake was assessed using a 203-item food frequency questionnaire., Results: Participants had a mean age of 55 years and 74% were women. The intake of vegetable protein was significantly lower in CD patients than in healthy controls (mean difference of 7.8 g/d; 95% CI: 4.7-10.8), as were serum concentrations of tyrosine, phenylalanine and tryptophan (all p < 0.005). However, within the CD patient group, the presence of major depressive disorder (n = 42) was not associated with intake or serum levels of essential amino acids., Conclusions: Patients with CD on a long-term gluten-free diet, with good adherence, consume significantly less vegetable protein than controls, and their serum levels of several essential amino acids were also lower. Despite its potential adverse effect, intake and serum levels of essential amino acids were not related to major depression.

Objectives: Celiac disease (CD), a genetically predisposed intolerance for gluten, is associated with an increased risk of major depressive disorder (MDD). We investigated whether dietary intake and serum levels of the essential n-3 polyunsaturated fatty acids (PUFA) eicosapentaenoic acid (EPA) and docosahexanoic acid (DHA) found in fatty fish play a role in this association., Methods: Cross-sectional study in 71 adult CD patients and 31 healthy volunteers, matched on age, gender and level of education, who were not using n-3 PUFA supplements. Dietary intake, as assessed using a 203-item food frequency questionnaire, and serum levels of EPA and DHA were compared in analyses of covariance, adjusting for potential confounders. Serum PUFA were determined using gas chromatography., Results: Mean serum DHA was significantly higher in CD patients (1.72 mass%) than controls (1.28 mass%) after multivariable adjustment (mean diff. 0.45 mass%; 95% CI: 0.22-0.68; p = 0.001). The mean intake of EPA plus DHA did not differ between CD patients and controls after multivariable adjustment (0.15 and 0.22 g/d, respectively; p = 0.10). There were no significant differences in intake or serum levels of EPA and DHA between any of the CD patient groups (never depressed, current MDD, minor/partially remitted MDD, remitted MDD) and controls., Conclusions: Patients on a long term gluten-free diet had similar intakes of EPA plus DHA compared to controls. Contrary to expectations, DHA serum levels were significantly higher in CD patients compared to healthy controls and were unrelated to MDD status.

Background: Cognitive reactivity to sad mood is a vulnerability marker of depression. Implicit self-depressed associations are related to depression status and reduced remission probability. It is unknown whether these cognitive vulnerabilities precede the first onset of depression., Aim: To test the predictive value of cognitive reactivity and implicit self-depressed associations for the incidence of depressive disorders., Methods: Prospective cohort study of 834 never-depressed individuals, followed over a two-year period. The predictive value of cognitive reactivity and implicit self-depressed associations for the onset of depressive disorders was assessed using binomial logistic regression. The multivariate model corrected for baseline levels of subclinical depressive symptoms, neuroticism, for the presence of a history of anxiety disorders, for family history of depressive or anxiety disorders, and for the incidence of negative life events., Results: As single predictors, both cognitive reactivity and implicit self-depressed associations were significantly associated with depression incidence. In the multivariate model, cognitive reactivity was significantly associated with depression incidence, together with baseline depressive symptoms and the number of negative life events, whereas implicit self-depressed associations were not., Conclusion: Cognitive reactivity to sad mood is associated with the incidence of depressive disorders, also when various other depression-related variables are controlled for. Implicit self-depressed associations predicted depression incidence in a bivariate test, but not when controlling for other predictors.

Background. Attention bias modification (ABM) is a new treatment for affective disorders. A meta-analysis of ABM for anxiety disorders showed that the effect size may be large but the number of studies is low. The working mechanism is still unclear, and little is known about the optimal treatment parameters. ABM for depression is much less studied. A few studies claimed positive effects but the sample sizes are low. Furthermore, the treatment parameters varied widely and differed from the anxiety literature. Aim. To select the most promising version of ABM for depression for further evaluation in clinical trials. Methods. Multiple case series design. We tested six versions of ABM that varied on stimulus duration and training direction. Thirty students with mild to moderate symptoms of depression underwent four sessions of ABM. Change of attentional bias was measured during each session. Generalization of treatment effects and the role of awareness of receiving training were also investigated. Results. None of the investigated versions of ABM had a consistent effect on attentional bias. Changes of attentional bias in individual participants the effects did not generalize to untrained stimuli. Conclusion. It is unlikely that any of these ABM versions will have a specific effect on symptoms in controlled studies.

Acute tryptophan depletion (ATD) induces depressive symptoms in 50-60% of selective serotonin reuptake inhibitor (SSRI) treated, recovered depressed patients. However, no reliable predictors of mood response to ATD have been established. In the present study, individual subject data of six ATD studies were pooled ('mega-analysis') in order to investigate the mediating role of clinical, demographic and biochemical characteristics in the mood response to ATD. A procedure was developed to make different versions of the Hamilton scale comparable. Recurrent depressive episodes, female gender, prior exposure to SSRI antidepressant treatment and previous serious suicidal thoughts/attempts all appear to be independent predictors of mood response to ATD. Chronicity of illness is the most powerful predictor. Residual symptoms of depression were not found to predict response to ATD. ATD may be useful to study the mechanism of action of SSRI antidepressants and individual biological vulnerability of the serotonin system. Whether the effects of ATD represent a reversal of the action of SSRI antidepressants or individual vulnerability probably depends upon the timing of the procedure in the course of remission of a depressive episode.