Fatty acids and recurrence of major depressive disorder: combined analysis of two Dutch clinical cohorts.

OBJECTIVE: Omega-3 (n-3) and omega-6 (n-6) polyunsaturated fatty acid (PUFA) alterations in patients with major depressive disorder (MDD) have been shown to persist after remission. Whether these alterations are risk factors for MDD recurrence remains unknown. Here, we examined whether fatty acids predict time until MDD recurrence in remitted MDD patients. METHODS: Data were used from remitted MDD patients of the Netherlands Study of Depression and Anxiety (n = 356) and the Depression Evaluation Longitudinal Therapy Assessment studies (n = 118). Associations of FAs with time until MDD recurrence up to 8-year follow-up were analyzed using Cox regression analyses. Study-specific estimates were pooled using mega- and meta-analysis techniques. RESULTS: 27.5% (NESDA) and 56.8% (DELTA) participants had an MDD recurrence. Pooled results showed that no FA was significantly associated with time until MDD recurrence (n-3 PUFAs: hazard ratio (HR) = 1.17, 95% confidence interval (CI) = 0.98-1.41, P = 0.082; n-6 PUFAs: HR = 1.08, 95% CI = 0.84-1.38, P = 0.55). CONCLUSION: In remitted MDD patients, circulating PUFAs were not associated with prospective risk of MDD recurrence. Consequently, circulating PUFAs are unlikely to reflect a vulnerability marker for recurrence, so correcting n-3 PUFA 'deficits' through supplementation does not seem a promising option to prevent MDD recurrence.

[Antidepressants are frequently prescribed but still critized; a perspective on causes and solutions]. / Antidepressiva: al decennia voor­geschreven én toch nog steeds bekritiseerd; een perspectief op oorzaken en oplossingen.

BACKGROUND: From around 1980, antidepressants (ad) have increasingly been prescribed, for longer periods of time, especially selective serotonin reuptake inhibitors (ssris). Paradoxically, their effectiveness is still doubted, especially outside the psychiatric profession.
AIM: To explain increase and offer a perspective on causes and solutions, and to indicate how to reach consensus.
METHOD: Position paper with critical analysis and synthesis of relevant literature.
RESULTS: The rise in AD prescriptions results from: 1. increased safety and ease of prescribing, 2. increased presentation and recognition of depression in primary care, 3. extension of indication criteria, 4. effective marketing strategies, and 5. effectiveness in acute phase (aad) and of relapse/recurrence prevention in continuation/maintenance phases (coad).Critics point to: 1. low added value of aad relative to placebo, 2. many drop-outs and non-responders, 3. relapse/recurrence prevention with coad works only for responders to aad, 4. relapse/recurrence after AD discontinuation often involves withdrawal symptoms, and 5. publication bias, selective reporting, selective patient selection, and suboptimal blinding, resulting in overestimated effectiveness and underestimated disadvantages.Factors that keep fueling the controversy are: 1. critics stress the net effectiveness of AD whereas proponents point at gross effectiveness which includes spontaneous recovery and placebo effect; 2. persistence of distrust in industry-funded rcts; 3. ideological positions, reinforced by conflicts of interest and selective citations; 4. lack of rcts with relevant long-term outcome measurements.
CONCLUSION: Although consensus is difficult to achieve given the ideological component, there are options. Three factors are critically important: confer to establish which data convince the opposition, response prediction (what works for whom), and rcts with long-term functional outcomes.

Predictive accuracy of Edinburgh postnatal depression scale assessment during pregnancy for the risk of developing postpartum depressive symptoms: a prospective cohort study.

OBJECTIVE: To investigate whether the 10-item Edinburgh Postnatal Depression Scale (EPDS) administered antenatally is accurate in predicting postpartum depressive symptoms, and whether a two-item EPDS has similar predictive accuracy. DESIGN: Prospective cohort study. SETTING: Obstetric care in the Netherlands. POPULATION: One thousand six hundred and twenty women from the general population. METHODS: Mean values, area under the receiver operating characteristics curve (AUC), sensitivity, specificity and predictive values of antenatal EPDS for the likelihood of developing postpartum depressive symptoms were calculated. Analyses were repeated for each trimester, several cut-off values and a two-item EPDS (low mood and anhedonia). MAIN OUTCOME MEASURES: Postpartum depressive symptoms, defined as EPDS score≥10. RESULTS: Mean EPDS scores were significantly higher during each trimester in women with postpartum depressive symptoms than in those without the symptoms (P<0.001). Using the prevailing cut-off (≥13), the AUC was reasonable (0.74), sensitivity was 16.8% (95% CI 11.0-24.1), positive predictive value was 41.8% (95% CI 28.7-55.9), specificity was 97.8% (95% CI 97.0-98.5) and negative predictive value was 92.7% (95% CI 91.3-94.0). Using a lower cut-off value (≥5), sensitivity was 70.8% (95% CI 62.4-78.3) and specificity was 65.4% 4 (95% CI 62.9-67.8), but positive predictive value was low (15.9%, 95% CI 13.1-19.0). Negative predictive value was exceedingly high at 96.0% (95% CI 94.6-97.2). Results were similar during the second and third trimester. The predictive accuracy of the two-item EPDS appeared inferior. CONCLUSIONS: The EPDS was not sufficiently accurate in predicting risk of postpartum depressive symptoms. Nevertheless, when using the ≥5 cut-off value, it may be adequate for initial screening, followed by further assessments and possibly antenatal intervention when positive. Furthermore, when negative, women may be reassured that postpartum depressive symptoms are unlikely. A two-item version showed poor predictive accuracy.

Electroencephalography for predicting antidepressant treatment success: A systematic review and meta-analysis.

BACKGROUND: Patients suffering from major depressive disorder (MDD) regularly experience non-response to treatment for their depressive episode. Personalized clinical decision making could shorten depressive episodes and reduce patient suffering. Although no clinical tools are currently available, machine learning analysis of electroencephalography (EEG) shows promise in treatment response prediction. METHODS: With a systematic review and meta-analysis, we evaluated the accuracy of EEG for individual patient response prediction. Importantly, we included only prediction studies that used cross-validation. We used a bivariate model to calculate prediction success, as expressed by area-under the curve, sensitivity and specificity. Furthermore, we analyzed prediction success for separate antidepressant interventions. RESULTS: 15 studies with 12 individual patient samples and a total of 479 patients were included. Research methods varied considerably between studies. Meta-analysis of results from this heterogeneous set of studies resulted in an area under the curve of 0.91, a sensitivity of 83 % (95 % CI 74-89 %), and a specificity of 86 % (95 % CI 81-90 %). Classification performance did not significantly differ between treatments. Although studies were all internally validated, no externally validated studies have been reported. We found substantial risk of bias caused by methodological shortcomings such as non-independent feature selection, though performance of non-biased studies was comparable. LIMITATIONS: Sample sizes were relatively small and no study used external validation, increasing the risk of overestimation of accuracy. CONCLUSIONS: Electroencephalography can predict the response to antidepressant treatment with high accuracy. However, future studies with more rigorous validation are needed to produce a clinical tool to guide interventions in MDD. PROSPERO REGISTRATION NUMBER: CRD42021268169.

Cortisol, dehydroepiandrosterone sulfate, fatty acids, and their relation in recurrent depression.

BACKGROUND: Alterations in hypothalamic-pituitary-adrenal (HPA)-axis activity, fatty acid metabolism, and their relation have been associated with (recurrent) major depressive disorder (MDD), although conflicting findings exist. AIMS: To determine whether alterations in HPA-axis activity and fatty acids in recurrent MDD remain during remission (i.e. reflect a potential trait factor). Furthermore, to test the association between HPA-axis activity and fatty acids in patients versus controls. METHODS: We cross-sectionally compared 73 remitted unmedicated recurrent MDD patients with 46 matched never-depressed controls. Measurements included salivary cortisol and dehydroepiandrosterone sulfate (DHEAS) (awakening, evening, and after sad mood induction) and erythrocyte fatty acid parameters: (I) three main fatty acids [omega-3 docosahexaenoic acid (DHA), and the omega-3 eicosapentaenoic acid/omega-6 arachidonic acid (EPA/AA)-ratio], and (II) structural fatty acid indices [chain length, unsaturation and peroxidation]. RESULTS: Patients showed higher cortisol awakening responses (p = 0.006) and lower evening cortisol/DHEAS ratios (p = 0.044) compared to matched controls. Fatty acids did not differ between patients and controls, but HPA-axis indicators were significantly associated with fatty acid parameters in both groups (0.001 ≤ p ≤ 0.043). Patients and controls significantly differed in the relations between awakening DHEAS or cortisol/DHEAS ratios and fatty acid parameters, including unsaturation and peroxidation indices (0.001≤ p ≤ 0.034). Significance remained after correction for confounders. CONCLUSIONS: Our results further support alterations in HPA-axis activity, i.e. a lower baseline, but higher responsiveness of awakening cortisol, in remitted medication-free recurrent MDD patients. Furthermore, the relationship between HPA-axis and fatty acids showed significant differences in recurrent MDD patients versus controls. Prospective research is needed to determine the predictive value of this relationship for MDD recurrence.

Prenatal maternal psychopathology and stress and offspring HPA axis function at 6 years.

OBJECTIVE: Intrauterine exposures such as maternal psychopathology and stress are known to influence the physical and mental health of the offspring. One of the proposed pathways underlying these associations is dysregulated hypothalamic-pituitary-adrenal (HPA) axis activity in the offspring. This study examined the relation of perinatal maternal symptoms of psychopathology and stress with offspring HPA axis activity at 6 years as measured by hair cortisol and cortisone concentrations. METHODS: The study was part of the population-based Generation R Study, a prospective population-based cohort from fetal life onwards. 2546 children and their mothers formed the study population. Perinatal maternal psychopathology and stress were assessed by questionnaires in the second and third trimester. Principal components for both psychopathology and stress were created to reduce the number of explanatory variables. Child hair samples for cortisol and cortisone measurements were collected at the age of 6. Linear regression analysis, adjusted for covariates, was used to examine associations between maternal psychopathology and stress and child hair cortisol and cortisone levels. RESULTS: The maternal psychopathology principal component was associated with higher child hair cortisone (adjusted B = 0.24, 95%CI 0.08;0.40, p-value < 0.01). Effect estimates of the individual dimensions ranged from 0.97 (95%CI 0.21;1.73, p-value = 0.01) for interpersonal sensitivity to 1.67 (95%CI 0.86;2.47, p-value < 0.01) for paranoid ideation. In addition, children exposed to intrauterine stress, as measured by the principal component, had higher hair cortisone levels (adjusted B = 0.54, 95%CI 0.21;0.88, p-value < 0.01). Exposure to maternal psychopathology and stress was not associated with offspring hair cortisol. Stratification by child sex resulted in associations between maternal symptoms of psychopathology during pregnancy and child hair cortisone levels in boys and associations between maternal symptoms of stress during pregnancy and child hair cortisone levels in girls. CONCLUSION: Our results suggest that maternal psychopathology and stress during pregnancy are associated with long-term HPA axis activity of the offspring. The association of maternal psychopathology and stress during pregnancy with offspring hair cortisone levels is a novel finding. Future studies should examine whether these psychophysiological differences between exposed and non-exposed children underlie offspring morbidity associated with maternal psychopathology and stress during pregnancy.

[Selective publication of research into antidepressants: consequences for the practice guideline 'depression']. / Selectieve publicatie van onderzoek met antidepressiva: gevolgen voor de richtlijn 'depressie'.

It was recently shown in a publication in The New England Journal of Medicine that the publicly accessible information about the effectiveness of antidepressive medication is incomplete and biased. The authors calculated from published and unpublished data that the effectiveness of antidepressants as published in the literature is overestimated probably by 32%. Based on this publication and other publications questioning the effectiveness of antidepressants, adjustment of the Dutch practice guideline for depression is proposed: only severely depressed patients should be treated with antidepressants. Some measures to prevent publication bias are also proposed. These require the cooperation of all parties participating in registration ofdrugs and publication of drug research.

Prevalence and predictors of violent victimization in remitted patients with recurrent depression.

BACKGROUND: Depressed patients are at increased risk to fall victim to a violent crime compared to the general population. It remains unknown whether their increased risk persists after remission. This study compared victimization rates of remitted patients with both a random general population sample and a group of currently depressed patients. Furthermore, this study aimed to identify predictors of future violent victimization. METHODS: In this longitudinal study conducted in the Netherlands, 12-month prevalence rates of sexual assaults, physical assaults, and threats were assessed with the Safety Monitor in 140 currently remitted patients with recurrent depression, and compared to those of a weighted general population sample (N = 9.175) and a weighted sample of currently depressed outpatients (N = 102) using Chi-square tests. Logistic regression analyses were performed to identify baseline predictors of future victimization. RESULTS: The prevalence of violent victimization did not differ between remitted patients and the general population (12.1 vs. 11.7%). Remitted patients were significantly less likely to have been victimized over the past 12 months than currently depressed patients (12.1 vs. 35.5%). In remitted patients, living alone and low sense of mastery at baseline predicted future violent victimization. However, when combined in a multiple model, only living alone was independently associated with violent victimization (χ2 = 16.725, df = 2, p < .001, R2 = 0.221). LIMITATIONS: Our comparison of victimization rates across samples was cross-sectional. CONCLUSIONS: Since the increased risk of victimization appears to be specific for the acute depressive state, preventive interventions should target victimization in currently depressed patients. TRIAL REGISTRATION: Netherlands Trial Register (NTR): 2599.

What are the effects of preventative interventions on major depressive disorder (MDD) in young adults? A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Depression is a prevalent disorder with a peak rate of onset in young adulthood from 18 to 25 years. To date, no review has systematically assessed the effectiveness of programs that aim to reduce depressive symptoms or diagnosis of depression in young adults. METHOD: A systematic search was performed in Cochrane, PubMed, PsycINFO and EMBASE. We performed a random-effects meta-analysis of the randomized controlled studies that compared an intervention for young adults (aged 18-25) without a diagnosis or history of depression and a control condition. Comparisons between intervention and control group outcomes were carried out at the post-intervention time point. We also compared intervention and control group outcomes at later follow-up time points where data were available. RESULTS: Twenty-six randomized controlled trials among 2865 young adults were included in the analysis. The pooled effect size of the interventions versus control at post-intervention was g = 0.37 (95% CI: 0.28-0.47, NNT = 9) and heterogeneity was moderate I2 = 36 (95% CI: 11-64). There were no significant effects in terms of the type of delivery, focus of study, type of control, or type of support within the interventions. LIMITATIONS: The authors were unable to assess the effects of interventions on the onset of depression as none of the included studies measured incidence. The risk of bias was high in most studies (81%). Only one study included a follow-up of more than a year. Demographic factors were inconsistently reported in the included articles. CONCLUSION: While it was not possible to investigate the effects of interventions on depression incidence, some evidence was found for the effectiveness of preventative interventions in reducing depressive symptoms in young adults. Future research should address limitations of the current evidence base to allow stronger conclusions to be drawn.

The role of affect in predicting depressive symptomatology in remitted recurrently depressed patients.

BACKGROUND: Major depressive disorder is an emotional disorder. It is important to improve our understanding of the role of affect in relapse/recurrence of depression. Therefore, this study examines whether affect plays a role in prospectively predicting depressive symptomatology and if there are indications for emotional scarring as a consequence of undergoing depressive episodes. METHODS: In 107 patients remitted from recurrent depression affect was examined in predicting depressive symptomatology as measured with the Inventory of Depressive Symptomatology - Self Report. Affect was measured with the Positive and Negative Affect Schedule and with a one item Visual Analogue Mood Scale. Indication of emotional scarring was examined by comparing number of previous depressive episodes to levels of affect. RESULTS: Less positive affect as assessed after remission predicted increased depressive symptomatology six months later, even after we controlled for baseline symptomatology. Negative affect also predicted depressive symptomatology six months later, but not after controlling for baseline depressive symptomatology. No relationship was found between affect and number of previous episodes. LIMITATIONS: All participants in this study had two or more previous depressive episodes and received CBT during the acute phase of their depression. The instruments that measured mood and affect were administered within 4 weeks of each other. CONCLUSIONS: Positive affect and negative affect as assessed after remission in recurrent depression can predict depressive symptomatology. Especially positive affect seems to play an independent role in predicting depressive symptomatology. Directly targeting positive affect in relapse prevention during remission might be a way to enhance treatment effects.

The potential of low-intensity and online interventions for depression in low- and middle-income countries.

The World Health Organization (WHO) reports that low- and middle-income countries (LMICs) are confronted with a serious 'mental health gap', indicating an enormous disparity between the number of individuals in need of mental health care and the availability of professionals to provide such care (WHO in 2010). Traditional forms of mental health services (i.e. face-to-face, individualised assessments and interventions) are therefore not feasible. We propose three strategies for addressing this mental health gap: delivery of evidence-based, low-intensity interventions by non-specialists, the use of transdiagnostic treatment protocols, and strategic deployment of technology to facilitate access and uptake. We urge researchers from all over the world to conduct feasibility studies and randomised controlled studies on the effect of low-intensity interventions and technology supported (e.g. online) interventions in LMICs, preferably using an active control condition as comparison, to ensure we disseminate effective treatments in LMICs.

A systematic review of online interventions for mental health in low and middle income countries: a neglected field.

BACKGROUND: Low and middle income countries (LMICs) are facing an increase of the impact of mental health problems while confronted with limited resources and limited access to mental health care, known as the 'mental health gap'. One strategy to reduce the mental health gap would be to utilize the internet to provide more widely-distributed and low cost mental health care. We undertook this systematic review to investigate the effectiveness and efficacy of online interventions in LMICs. METHODS: We systematically searched the data-bases PubMed, PsycINFO, JMIR, and additional sources. MeSH terms, Thesaurus, and free text keywords were used. We included all randomized controlled trials (RCTs) of online interventions in LMICs. RESULTS: We found only three articles reported results of RCTs on online interventions for mental health conditions in LMICs, but none of these interventions was compared with an active control condition. Also, the mental health conditions were diverse across the three studies. CONCLUSIONS: There is a dearth of studies examining the effect of online interventions in LMICs, so we cannot draw a firm conclusion on its effectiveness. However, given the effectiveness of online interventions in high income countries and sharp increase of internet access in LMICs, online interventions may offer a potential to help reduce the 'mental health gap'. More studies are urgently needed in LMICs.

Interaction between the MTHFR C677T polymorphism and traumatic childhood events predicts depression.

Childhood trauma is associated with the onset and recurrence of major depressive disorder (MDD). The thermolabile T variant of the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism (rs1801133) is associated with a limited (oxidative) stress defense. Therefore, C677T MTHFR could be a potential predictor for depressive symptomatology and MDD recurrence in the context of traumatic stress during early life. We investigated the interaction between the C677T MTHFR variant and exposure to traumatic childhood events (TCEs) on MDD recurrence during a 5.5-year follow-up in a discovery sample of 124 patients with recurrent MDD and, in an independent replication sample, on depressive symptomatology in 665 healthy individuals from the general population. In the discovery sample, Cox regression analysis revealed a significant interaction between MTHFR genotype and TCEs on MDD recurrence (P=0.017). Over the 5.5-year follow-up period, median time to recurrence was 191 days for T-allele carrying patients who experienced TCEs (T+ and TCE+); 461 days for T- and TCE+ patients; 773 days for T+ and TCE- patients and 866 days for T- and TCE- patients. In the replication sample, a significant interaction was present between the MTHFR genotype and TCEs on depressive symptomatology (P=0.002). Our results show that the effects of TCEs on the prospectively assessed recurrence of MDD and self-reported depressive symptoms in the general population depend on the MTHFR genotype. In conclusion, T-allele carriers may be at an increased risk for depressive symptoms or MDD recurrence after exposure to childhood trauma.

Do Inflammatory Bowel Disease patients with anxiety and depressive symptoms receive the care they need?

BACKGROUND AND AIMS: Inflammatory Bowel Disease (IBD) patients with anxiety and/or depressive symptoms may not receive the care they need. Provision of care requires insight into the factors affecting these psychiatric symptoms. The study was designed to examine the extent to which: (1) IBD patients with anxiety and/or depressive symptoms receive mental treatment and (2) clinical and socio-demographic variables are associated with these symptoms. METHODS: 231 adult IBD patients (79% response rate), attending a tertiary care center, completed standardized measures on anxiety and depressive symptoms (HADS), quality of life (SF-12) and mental health care use (TIC-P). Diagnosis and disease activity were determined by the gastroenterologist. RESULTS: 43% had high levels of anxiety and/or depressive symptoms, indicative of a psychiatric disorder (HADS ≥ 8), of whom 18% received psychological treatment and 21% used psychotropic medication. In multivariate analysis, high disease activity was associated with anxiety (OR=2.72 | p<0.03) and depression (OR=3.36 | p<0.01), while Crohn's disease was associated with anxiety (OR=2.60 | p<0.03). CONCLUSIONS: Despite high levels of anxiety and depressive symptoms and poor quality of life, psychiatric complaints in IBD patients were undertreated. Screening for and treatment of psychiatric symptoms should become an integral part of IBD medical care.