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Reliable predictors for electroconvulsive therapy (ECT) effectiveness would allow a more precise and personalized approach for the treatment of major depressive disorder (MDD). Prediction models were created using a priori selected clinical variables based on previous meta-analyses. Multivariable linear regression analysis was used, applying backwards selection to determine predictor variables while allowing non-linear relations, to develop a prediction model for depression outcome post-ECT (and logistic regression for remission and response as secondary outcome measures). Internal validation and internal-external cross-validation were used to examine overfitting and generalizability of the model's predictive performance. In total, 1892 adult patients with MDD were included from 22 clinical and research cohorts of the twelve sites within the Dutch ECT Consortium. The final primary prediction model showed several factors that significantly predicted a lower depression score post-ECT: higher age, shorter duration of the current depressive episode, severe MDD with psychotic features, lower level of previous antidepressant resistance in the current episode, higher pre-ECT global cognitive functioning, absence of a comorbid personality disorder, and a lower level of failed psychotherapy in the current episode. The optimism-adjusted R² of the final model was 19%. This prediction model based on readily available clinical information can reduce uncertainty of ECT outcomes and hereby inform clinical decision-making, as prompt referral for ECT may be particularly beneficial for individuals with the above-mentioned characteristics. However, despite including a large number of pretreatment factors, a large proportion of the variance in depression outcome post-ECT remained unpredictable., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Monitoring cognitive side-effects following electroconvulsive therapy (ECT) is crucial for balancing side-effects and clinical effectiveness. Unfortunately, evidence-based guidelines on cognitive testing following ECT are lacking. A frequently used test in global ECT practice is the Mini Mental State Examination (MMSE). We examined the change of the MMSE and its performance in identifying a decline in predefined neuropsychological measures sensitive to ECT-induced cognitive changes: verbal recall and verbal fluency., Methods: The mean MMSE scores pre- and one week post-ECT were compared using a Wilcoxon signed-rank test. The Reliable Change Index was calculated for all cognitive measures to indicate whether an individual's change score from pre- to post-ECT is considered statistically significant. The sensitivity and specificity of the MMSE were calculated., Results: 426 patients with depression from five sites were included from the Dutch ECT Consortium. The mean MMSE increased significantly from 26.2 (SD=3.9) pre-ECT to 26.8 (SD=3.8) post-ECT (p=0.002). 36 patients (8.5%) showed a significant decline in MMSE score post-ECT. The sensitivity of the MMSE in identifying patients who experienced a significant decline in verbal recall or verbal fluency ranged from 3.6% to 11.1%. The specificity of the MMSE in identifying patients who did not experience a significant decline in verbal recall or verbal fluency ranged from 95.6% to 96.6%., Conclusions: Given the very low sensitivity of the MMSE, we propose reconsidering the prominence of the MMSE in ECT practice and cognitive monitoring guidelines, advocating for a more comprehensive approach to assess ECT-induced cognitive changes., (Copyright © 2024. Published by Elsevier Inc.)

Background: Since 2013, deep brain stimulation (DBS) has been reimbursed in the Netherlands as a proven effective treatment for treatment-resistant obsessive-compulsive disorder (OCD). Nevertheless, DBS is still rarely applied, and a national Dutch treatment protocol is lacking., Aim: To prepare a nationwide multidisciplinary treatment protocol for the application of DBS in the treatment of treatment-resistant OCD., Method: Formulation of recommendations for the execution and application of DBS in OCD regarding indication, implantation, optimization of stimulation parameters, and consolidation of long-term effects, based on literature research and consensus among experts represented in the multidisciplinary Dutch DBS in Psychiatry working group., Results: Following indication, DBS electrodes are bilaterally implanted in white matter tracts in the anterior limb of the internal capsule. In previously highly treatment-resistant patients with severe OCD, this leads to an average 66% response rate after optimization of stimulation parameters. Placebo-controlled effects are significant (Hedges’ g = 0.9). The main reported side effects are transient hypomanic symptoms, fatigue, and subjective cognitive complaints. Perioperative complications are rare. Positive effects remain stable during years of follow-up. DBS is cost-effective and leads to increased quality of life and functional recovery. Nevertheless, DBS is applied infrequently relative to the estimated number of patients with treatment-resistant OCD., Conclusion: By adhering to the described recommendations regarding indication, implantation, optimization, and consolidation, DBS is an effective and safe treatment option for treatment-resistant OCD. A nationwide multidisciplinary treatment protocol can contribute to the implementation of DBS with more and earlier referrals, allowing more patients to benefit from this treatment more quickly.

Recurrence in major depressive disorder (MDD) is common, but neurobiological models capturing vulnerability for recurrences are scarce. Disturbances in multiple resting-state networks have been linked to MDD, but most approaches focus on stable (vs. dynamic) network characteristics. We investigated how the brain's dynamical repertoire changes after patients transition from remission to recurrence of a new depressive episode. Sixty two drug-free, MDD-patients with ≥2 episodes underwent a baseline resting-state fMRI scan when in remission. Over 30-months follow-up, 11 patients with a recurrence and 17 matched-remitted MDD-patients without a recurrence underwent a second fMRI scan. Recurrent patterns of functional connectivity were characterized by applying Leading Eigenvector Dynamics Analysis (LEiDA). Differences between baseline and follow-up were identified for the 11 non-remitted patients, while data from the 17 matched-remitted patients was used as a validation dataset. After the transition into a depressive state, basal ganglia-anterior cingulate cortex (ACC) and visuo-attentional networks were detected significantly more often, whereas default mode network activity was found to have a longer duration. Additionally, the fMRI signal in the basal ganglia-ACC areas underlying the reward network, were significantly less synchronized with the rest of the brain after recurrence (compared to a state of remission). No significant changes were observed in the matched-remitted patients who were scanned twice while in remission. These findings characterize changes that may be associated with the transition from remission to recurrence and provide initial evidence of altered dynamical exploration of the brain's repertoire of functional networks when a recurrent depressive episode occurs., (© 2023 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Background: Anorexia nervosa (AN) is a severe and life-threatening psychiatric disorder. Initial studies on deep brain stimulation (DBS) in severe, treatment-refractory AN have shown clinical effects. However, the working mechanisms of DBS in AN remain largely unknown. Here, we used a task-based functional MRI approach to understand the pathophysiology of AN., Methods: We performed functional MRI on four AN patients that participated in a pilot study on the efficacy, safety, and functional effects of DBS targeted at the ventral limb of the capsula interna (vALIC). The patients and six gender-matched healthy controls (HC) were investigated at three different time points. We used an adapted version of the monetary incentive delay task to probe generic reward processing in patients and controls, and a food-specific task in patients only., Results: At baseline, no significant differences for reward anticipation were found between AN and HC. Significant group (AN and HC) by time (pre- and post-DBS) interactions were found in the right precuneus, right putamen, right ventral and medial orbitofrontal cortex (mOFC). No significant interactions were found in the food viewing task, neither between the conditions high-calorie and low-calorie food images nor between the different time points. This could possibly be due to the small sample size and the lack of a control group., Conclusion: The results showed a difference in the response of reward-related brain areas post-DBS. This supports the hypotheses that the reward circuitry is involved in the pathogenesis of AN and that DBS affects responsivity of reward-related brain areas. Trial registration Registered in the Netherlands Trial Register ( https://www.trialregister.nl/trial/3322 ): NL3322 (NTR3469)., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Polyunsaturated fatty acids (PUFAs) have important electrochemical properties and have been implicated in the pathophysiology of major depressive disorder (MDD) and its treatment. However, the relation of PUFAs with electroconvulsive therapy (ECT) has never been investigated. Therefore, we aimed to explore the associations between PUFA concentrations and response to ECT in patients with MDD. We included 45 patients with unipolar MDD in a multicentre study. To determine PUFA concentrations, we collected blood samples at the first (T0) and twelfth (T12) ECT-session. We assessed depression severity using the Hamilton Rating Scale for Depression (HAM-D) at T0, T12 and at the end of the ECT-course. ECT-response was defined as 'early response' (at T12), 'late response' (after ECT-course) and 'no' response (after the ECT-course). The PUFA chain length index (CLI), unsaturation index (UI) and peroxidation index (PI) and three individual PUFAs (eicosapentaenoic acid [EPA], docosahexaenoic acid [DHA] and nervonic acid [NA]) were associated with response to ECT using linear mixed models. Results showed a significant higher CLI in 'late responders' compared to 'non responders'. For NA, 'late responders' showed significantly higher concentrations compared to 'early'- and 'non responders'. In conclusion, this study provides the first indication that PUFAs are associated with the efficacy of ECT. This indicates that PUFAs' influence on neuronal electrochemical properties and neurogenesis may affect ECT outcomes. Thereby, PUFAs form a potentially modifiable factor predicting ECT outcomes, that warrants further investigation in other ECT-cohorts., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Yearly, almost six percent, which is more than 1,000.000 people, in the Netherlands receive mental health treatment, which usually improves their quality of life. Concurrently, mental healthcare professionals recognize clinically refractory cases in which improvement fails to occur, with severe ongoing burdens for patients. The Dutch Centre for Consultation and Expertise (CCE) is available to support such refractory cases. The Dutch government's (financial) facilitation of consultation through the CCE is unique in the world. CCE consultations provide therefore unique insight into and an overview of refractory cases in mental health services. The objective of this study was to gain insight into the commonalities underlying the reasons for CCE consultations and the solutions proposed that play roles in (the reduction of) refractory cases for which consultation has been requested., Methods: This descriptive study was conducted with quantitative and qualitative data from 472 CCE consultations in the Netherlands. Using descriptive statistics and thematic content analysis, four exemplary situations were distilled from the qualitative data., Results: Most (83%) cases in the sample could be explained with four exemplary situations involving self-harm (24.2%), aggression (21.8%), self-neglect (24.4%), and socially unacceptable behavior (12.5%), respectively. Each situation could be characterized by a specific interaction pattern that unintentionally maintained or aggravated the situation. At the time of closure of the consultation applicants' questions had been answered and their situations had improved in 60.4% of cases., Conclusions: This study offers an overview of approaches that provided new perspectives for patients and professionals in many refractory cases in the Dutch mental health services., (© 2023. The Author(s).)

Background: Patients with psychiatric disorders often experience cognitive dysfunction, but the precise relationship between cognitive deficits and psychopathology remains unclear. We investigated the relationships between domains of cognitive functioning and psychopathology in a transdiagnostic sample using a data-driven approach., Methods: Cross-sectional network analyses were conducted to investigate the relationships between domains of psychopathology and cognitive functioning and detect clusters in the network. This naturalistic transdiagnostic sample consists of 1016 psychiatric patients who have a variety of psychiatric diagnoses, such as depressive disorders, anxiety disorders, obsessive-compulsive and related disorders, and schizophrenia spectrum and other psychotic disorders. Psychopathology symptoms were assessed using various questionnaires. Core cognitive domains were assessed with a battery of automated tests., Results: Network analysis detected three clusters that we labelled: general psychopathology, substance use, and cognition. Depressive and anxiety symptoms, verbal memory, and visual attention were the most central nodes in the network. Most associations between cognitive functioning and symptoms were negative, i.e. increased symptom severity was associated with worse cognitive functioning. Cannabis use, (subclinical) psychotic experiences, and anhedonia had the strongest total negative relationships with cognitive variables., Conclusions: Cognitive functioning and psychopathology are independent but related dimensions, which interact in a transdiagnostic manner. Depression, anxiety, verbal memory, and visual attention are especially relevant in this network and can be considered independent transdiagnostic targets for research and treatment in psychiatry. Moreover, future research on cognitive functioning in psychopathology should take a transdiagnostic approach, focusing on symptom-specific interactions with cognitive domains rather than investigating cognitive functioning within diagnostic categories.

Deep brain stimulation (DBS) of the ventral anterior limb of the internal capsule (vALIC) is effective for refractory obsessive-compulsive disorder (OCD). Retrospective evaluation showed that stimulation closer to the supero-lateral branch of the medial forebrain bundle (slMFB), within the vALIC, was associated with better response to DBS. The present study is the first to compare outcomes of DBS targeted at the vALIC using anatomical landmarks and DBS with connectomic tractography-based targeting of the slMFB. We included 20 OCD-patients with anatomical landmark-based DBS of the vALIC that were propensity score matched to 20 patients with tractography-based targeting of electrodes in the slMFB. After one year, we compared severity of OCD, anxiety and depression symptoms, response rates, time to response, number of parameter adjustments, average current, medication usage and stimulation-related adverse effects. There was no difference in Y-BOCS decrease between patients with anatomical landmark-based and tractography-based DBS. Nine (45%) patients with anatomical landmark-based DBS and 13 (65%) patients with tractography-based DBS were responders (BF 10  = 1.24). The course of depression and anxiety symptoms, time to response, number of stimulation adjustments or medication usage did not differ between groups. Patients with tractography-based DBS experienced fewer stimulation-related adverse effects than patients with anatomical landmark-based DBS (38 vs 58 transient and 1 vs. 17 lasting adverse effects; BF 10  = 14.968). OCD symptoms in patients with anatomical landmark-based DBS of the vALIC and tractography-based DBS of the slMFB decrease equally, but patients with tractography-based DBS experience less adverse effects., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Introduction: Each year almost 800.000 people die from suicide, of which up to 87% are affected by major depressive disorder (MDD). Despite the strong association between suicidality and MDD, it remains unknown if suicidal symptoms during remission put remitted recurrent MDD patients (rrMDD) at risk for recurrence., Methods: At baseline we compared sociodemographic characteristics and suicidal symptoms in un-medicated rrMDD participants to matched never-depressed controls. We used the HDRS 17 and IDS-SR 30 to assess suicidal symptoms and depressive symptomatology. Next, we studied the longitudinal association between baseline suicidal symptoms and time to recurrence(s) in rrMDD during a 2.5-year follow-up period using cox regression analyses. Further, we studied with longitudinal data whether suicidal symptoms and depressive symptomatology were cross-sectionally associated using mixed model analysis., Results: At baseline, rrMDD participants (N = 73) had higher self-reported suicidal symptoms than matched never-depressed controls (N = 45) (χ 2  = 12.09 p < .002). Self-reported suicidal symptoms were almost four times higher (27.9% versus 6.9%) compared to clinician-rated suicidal symptoms in rrMDD at baseline. Self-reported baseline suicidal symptoms, but not clinician-rated symptoms, predicted earlier MDD-recurrence during follow-up, independent of other residual depressive symptoms (χ 2  = 7.26, p < .026). Higher suicidal symptoms were longitudinally related to higher depressive symptoms (HDRS 17 ; F = 49.87, p < .001), IDS-SR 30 ; (F = 22.36, p < .001)., Conclusion: This study showed that self-reported - but not clinician-rated - suicidal symptoms persist during remission in rrMDD and predict recurrence, independent from residual symptoms. We recommend to monitor both suicidal and depressive symptomatology during remission in rrMDD, preferably also including self-reported questionnaires apart from clinician-rated. It would be beneficial for future research to assess suicidality using questionnaires primarily designed for measuring suicidal ideation., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Over two decades ago, the first scientific publication on deep brain stimulation (DBS) in psychiatry was published. The evidence for effectiveness of DBS for several psychiatric disorders has been steadily accumulating since the first report of DBS for Obsessive Compulsive Disorder (OCD) in 1999. However, the number of psychiatric patients treated with DBS is lagging behind, particularly in comparison with neurology. The number of patients treated with DBS for psychiatric indications worldwide probably does not exceed 500, compared to almost 300,000 patients with neurological disorders that have been treated with DBS within the same period of 20 years. It is not the lack of patients, knowledge, technology, or efficacy of DBS that hinders its development and application in psychiatry. Here, we discuss the reasons for the gap between DBS in neurology and in psychiatry, which seemed to involve the scientific and social signature of psychiatry., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Mocking, Graat and Denys.)

Background: Deep brain stimulation (DBS) for treatment-refractory obsessive-compulsive disorder (OCD) is effective in half of patients, but also is invasive and labor-intensive., Objective: Selecting probable responders beforehand would more optimally allocate treatment resources and prevent patients' disappointment. Some centers use clinical and demographic predictors to exclude patients from DBS treatment, but the evidence base remains uncertain., Methods: This observational cohort study examined the association of baseline demographic and disease characteristics with a 1-year prospective course of OCD and depressive symptoms in a cohort of 70 consecutive patients who received DBS of the ventral anterior limb of the internal capsule (vALIC-DBS) for OCD according to DSM-IV or DSM-5 criteria between April 2005 and October 2017. Baseline characteristics and symptom decrease were analyzed using Fisher exact tests and binary logistic regression to examine whether they could predict individual response (> 35% reduction in Yale-Brown Obsessive Compulsive Scale score and 50% reduction in Hamilton Depression Rating Scale score, respectively)., Results: Insight into illness was the only significant predictor of individual response, with a positive predictive value of 84.4%, while the negative predictive value was 44.0% ( b  = 0.247, χ 2 1  = 5.259, P  = .022). Late-onset OCD was associated with more symptom decrease (β = -0.29; 95% CI, -0.53 to -0.04; P  = .023) and comorbid personality disorder with less symptom decrease over time (β = 0.88; 95% CI -0.29 to 1.47; P  = .004), but they could not significantly predict vALIC-DBS response. A later age at onset, comorbid personality disorder, and insight into illness were associated with clinical outcomes after vALIC-DBS, but predictive values were not large enough to facilitate clinical patient selection., Conclusions: Clinical and demographic factors cannot yet predict outcome and should not be used to exclude patients from treatment with vALIC-DBS. These first individual prediction analyses for vALIC-DBS response in OCD are important, given that some centers up until now still exclude patients based on clinical characteristics such as comorbid personality disorders., (© Copyright 2021 Physicians Postgraduate Press, Inc.)

Objective: Several promising studies investigated marine omega-3 fatty acids (ie, fish oil) in borderline personality disorder (BPD), but overall effects remain unclear. The aim of this study was to obtain estimates of effectiveness of omega-3 fatty acids in BPD using meta-analysis, with a priori differentiation of affective, impulsive, and cognitive-perceptual symptom domains., Data Sources: We performed a literature search in PubMed, EMBASE, PsycINFO, and MEDLINE, using terms related to BPD and omega-3 fatty acids. Publication date was not a restriction., Study Selection: We included randomized controlled trials (RCTs) that compared omega-3 fatty acids to placebo or any active comparator and pooled data using meta-analysis. Five studies were included in the meta-analysis, describing 4 RCTs testing effects of omega-3 fatty acids in 137 patients with BPD or BPD-related behavior., Data Extraction: Using a pre-piloted data extraction form, we obtained data including intervention dose, duration, and BPD symptom scale scores, differentiating affective, impulsive, and cognitive-perceptual symptom domains., Results: Random effects meta-analysis showed an overall significant decreasing effect of omega-3 fatty acids on overall BPD symptom severity (0.54 standardized difference in means [SDM]; 95% CI = 0.91 to 0.17; Z = 2.87; P = .0041), without heterogeneity (I 2  = 0.00; Q = 2.63; P = .45). A priori differentiation of relevant symptom domains showed significant effects on affect dysregulation (0.74 SDM; 95% CI = 1.21 to 0.27; Z = 3.11; P = .002) and impulsive behavior (0.45 SDM; 95% CI = 0.84 to 0.059; Z = 2.26; P = .024). However, effects on cognitive-perceptual symptoms did not reach the significance threshold., Conclusions: Available data indicate that marine omega-3 fatty acids improve symptoms of BPD, particularly impulsive behavioral dyscontrol and affective dysregulation. Marine omega-3 fatty acids could be considered as add-on therapy., (© Copyright 2021 Physicians Postgraduate Press, Inc.)

Recurrent major depressive disorder (rMDD) is a relapsing-remitting disease with high morbidity and a 5-year risk of recurrence of up to 80%. This was a prospective pilot study to examine the potential diagnostic and prognostic value of targeted plasma metabolomics in the care of patients with rMDD in remission. We used an established LC-MS/MS platform to measure 399 metabolites in 68 subjects with rMDD (n = 45 females and 23 males) in antidepressant-free remission and 59 age- and sex-matched controls (n = 40 females and 19 males). Patients were then followed prospectively for 2.5 years. Metabolomics explained up to 43% of the phenotypic variance. The strongest biomarkers were gender specific. 80% of the metabolic predictors of recurrence in both males and females belonged to 6 pathways: (1) phospholipids, (2) sphingomyelins, (3) glycosphingolipids, (4) eicosanoids, (5) microbiome, and (6) purines. These changes traced to altered mitochondrial regulation of cellular redox, signaling, energy, and lipid metabolism. Metabolomics identified a chemical endophenotype that could be used to stratify rrMDD patients at greatest risk for recurrence with an accuracy over 0.90 (95%CI = 0.69-1.0). Power calculations suggest that a validation study of at least 198 females and 198 males (99 cases and 99 controls each) will be needed to confirm these results. Although a small study, these results are the first to show the potential utility of metabolomics in assisting with the important clinical challenge of prospectively identifying the patients at greatest risk of recurrence of a depressive episode and those who are at lower risk.

Background: Yearly, over 1.000.000 people receive mental health care treatment in the Netherlands. Treatment usually results in improvement in quality of life. Concurrently, each professional recognizes clinically refractory cases in which improvement fails to occur with severe ongoing burden for the client. In the Netherlands, for these clinically refractory cases the Centre of Consultation and Expertise (CCE) is available. The CCE is an independent nation-wide organisation offering free consultations to care providers. Therefore, CCE-consultations provide a unique insight in and overview of refractory cases., Aim: Providing overview of and insight into backgrounds and themes that play a role in (the reduction of) refractory cases., Method: Descriptive study of quantitative and qualitative data from 472 consultations in mental health care., Results: 83% of cases could be explained with 4 exemplary vignettes of refractoriness: self-harm, aggression, self-neglect and socially unacceptable behaviour., Conclusion: Refractory cases result from an interaction pattern that unintentionally maintains or aggravates the situation. This study offers an overview of approaches that proved to be helpful in providing new perspective for clients and professionals in many therapy refractory cases in Dutch mental health care.

It becomes increasingly clear that (non-)invasive neurostimulation is an effective treatment for obsessive-compulsive disorder (OCD). In this chapter we review the available evidence on techniques and targets, clinical results including a meta-analysis, mechanisms of action, and animal research. We focus on deep brain stimulation (DBS), but also cover non-invasive neurostimulation including transcranial magnetic stimulation (TMS). Data shows that most DBS studies target the ventral capsule/ventral striatum (VC/VS), with an overall 76% response rate in treatment-refractory OCD. Also TMS holds clinical promise. Increased insight in the normalizing effects of neurostimulation on cortico-striatal-thalamic-cortical (CSTC) loops - through neuroimaging and animal research - provides novel opportunities to further optimize treatment strategies. Advancing clinical implementation of neurostimulation techniques is essential to ameliorate the lives of the many treatment-refractory OCD patients., (© 2021. Springer Nature Switzerland AG.)

Objective: Several randomized controlled trials (RCTs) investigated omega-3 polyunsaturated fatty acids (PUFAs) (ie, fish oil) in perinatal depression, but their efficacy remains unclear. We performed a meta-analysis of RCTs on omega-3 PUFAs for perinatal depression, comparing a priori defined subgroups: pregnant women vs postpartum women and prevention vs treatment of perinatal depression., Methods: We searched Web of Science, Embase, PsycINFO, and the Cochrane Library, combining omega-3 PUFAs and perinatal depression terms and including publications up to February 18, 2019, for RCTs on omega-3 PUFAs compared to placebo or any active comparator., Results: Data from 18 RCTs on 4,052 participants showed an overall significant small beneficial effect of omega-3 PUFAs on depressive symptoms compared to placebo (-0.236 standardized difference in means [SDM]; 95% CI = -0.463 to -0.009; P = .042). Heterogeneity was considerable (I² = 88.58; P < .001), with significant subgroup differences explaining 55% of between-study variance (P = .001). In depressed women, omega-3 PUFAs showed a medium effect (SDM = -0.545; 95% CI = -1.182 to 0.093; P = .094) vs no effect in nondepressed women (SDM = -0.073). Moreover, the effect was medium to large in postpartum women (SDM = -0.656; 95% CI = -1.690 to 0.378; P = .214) compared to a negligible effect during pregnancy (SDM = -0.071). RCTs specifically studying postpartum depression showed the largest effect (SDM = -0.886; 95% CI = -2.088 to 0.316; P = .149)., Conclusions: Omega-3 PUFAs have an overall significant small beneficial effect on perinatal depression, with important subgroup differences. We advise against prescribing omega-3 PUFAs for the treatment or prevention of depressive symptoms during pregnancy, given a lack of effect with low heterogeneity. In contrast, omega-3 PUFA supplementation may be a promising (add-on) treatment for postpartum depression., (© Copyright 2020 Physicians Postgraduate Press, Inc.)

Background: Patients with psychiatric disorders, such as major depressive disorder, schizophrenia or obsessive-compulsive disorder, often suffer from cognitive dysfunction. The nature of these dysfunctions and their relation with clinical symptoms and biological parameters is not yet clear. Traditionally, cognitive dysfunction is studied in patients with specific psychiatric disorders, disregarding the fact that cognitive deficits are shared across disorders. The Across study aims to investigate cognitive functioning and its relation with psychiatric symptoms and biological parameters transdiagnostically and longitudinally., Methods: The study recruits patients diagnosed with a variety of psychiatric disorders and has a longitudinal cohort design with an assessment at baseline and at one-year follow-up. The primary outcome measure is cognitive functioning. The secondary outcome measures include clinical symptoms, electroencephalographic, genetic and blood markers (e.g., fatty acids), and hair cortisol concentration levels., Discussion: The Across study provides an opportunity for a transdiagnostic, bottom-up, data-driven approach of investigating cognition in relation to symptoms and biological parameters longitudinally in patients with psychiatric disorders. The study may help to find new clusters of symptoms, biological markers, and cognitive dysfunctions that have better prognostic value than the current diagnostic categories. Furthermore, increased insight into the relationship among cognitive deficits, biological parameters, and psychiatric symptoms can lead to new treatment possibilities., Trial Registration: Netherlands Trial Register (NTR): NL8170.

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., (© 2019 The Authors. Acta Psychiatrica Scandinavica Published by John Wiley & Sons Ltd.)

Background: Nutritional interventions are scarcely used in the prevention and treatment of mental disorders.
AIM: To summarize scientific evidence on the relation between nutrition and mental health, across the life span.
METHOD: An overview of the literature based on recent knowledge syntheses, meta-analyses and original studies.
RESULTS: Healthy dietary patterns are associated with a lower risk for depressive symptoms among adults and potentially also among children and adolescents. Dietary interventions can be effective in reducing depressive symptoms among high-risk groups and can have a beneficial effect in the treatment of depression. Meta-analyses of randomised studies have shown that omega-3 fatty acid supplements can be of added value in the treatment of adhd in children and of depression in adults.
CONCLUSION: Promotion of healthy dietary patterns in line with National guidelines for healthy diets is important in the entire spectrum from good mental health to a chronic disorder. More attention for improving healthy dietary patterns among patients with mental disorders can lead to important health gains.

Background: Depressive recurrence is highly prevalent and adds significantly to the burden of depressive disorder. Whilst some clinical predictors of recurrence have been clearly demonstrated (e.g. residual symptoms, previous episodes), the cognitive and psychological processes that may contribute to recurrence risk are less well established. In this study we examine whether cognitive flexibility deficits and rumination are related to recurrence in a remitted clinical sample., Method: We compared remitted patients with 2 or more previous depressive episodes (N = 69) to a matched group of healthy controls (N = 43). Cognitive flexibility was measured using the Internal Shift Task (IST) and a version of the Exogenous Cueing Task (ECT); rumination was assessed with the Ruminative Responses Scale., Results: IST and ECT performance did not differ between remitted patients and controls. Remitted patients had higher levels of rumination than controls. Within the remitted patient group, faster disengagement from angry and happy faces on the ECT was predictive of shorter time to recurrence (hazard ratio for 1 standard deviation, (HR SD ) = 0.563 [CI, 0.381-0.832], p = 0.004, (HR SD ) = 0.561 [CI, 0.389-0.808], p = 0.002, respectively). Rumination predicted recurrence (HR SD  = 1.526 [CI, 1.152-2.202]; p = 0.003) but was not related to emotional disengagement., Limitations: We had low power to detect small effects for the analysis within remitted patients., Conclusions: Whilst cognitive flexibility in remitted patients was not impaired relative to controls, rapid disengagement from emotional stimuli and rumination were independently associated with time to recurrence. Cognitive flexibility may be an important indicator of recurrence risk, and a target for interventions to reduce recurrence., (Copyright © 2019. Published by Elsevier B.V.)

One of the core symptoms of major depressive disorder is anhedonia, an inability to experience pleasure. In patients with major depressive disorder, a dysfunctional reward-system may exist, with blunted temporal difference reward-related learning signals in the ventral striatum and increased temporal difference-related (dopaminergic) activation in the ventral tegmental area. Anhedonia often remains as residual symptom during remission; however, it remains largely unknown whether the abovementioned reward systems are still dysfunctional when patients are in remission. We used a Pavlovian classical conditioning functional MRI task to explore the relationship between anhedonia and the temporal difference-related response of the ventral tegmental area and ventral striatum in medication-free remitted recurrent depression patients (n = 36) versus healthy control subjects (n = 27). Computational modelling was used to obtain the expected temporal difference errors during this task. Patients, compared to healthy controls, showed significantly increased temporal difference reward learning activation in the ventral tegmental area (PFWE,SVC = 0.028). No differences were observed between groups for ventral striatum activity. A group × anhedonia interaction [t(57) = -2.29, P = 0.026] indicated that in patients, higher anhedonia was associated with lower temporal difference activation in the ventral tegmental area, while in healthy controls higher anhedonia was associated with higher ventral tegmental area activation. These findings suggest impaired reward-related learning signals in the ventral tegmental area during remission in patients with depression. This merits further investigation to identify impaired reward-related learning as an endophenotype for recurrent depression. Moreover, the inverse association between reinforcement learning and anhedonia in patients implies an additional disturbing influence of anhedonia on reward-related learning or vice versa, suggesting that the level of anhedonia should be considered in behavioural treatments., (© The Author(s) (2019). Published by Oxford University Press on behalf of the Guarantors of Brain.)

Neurobiological models to explain vulnerability of major depressive disorder (MDD) are scarce and previous functional magnetic resonance imaging studies mostly examined "static" functional connectivity (FC). Knowing that FC constantly evolves over time, it becomes important to assess how FC dynamically differs in remitted-MDD patients vulnerable for new depressive episodes. Using a recently developed method to examine dynamic FC, we characterized re-emerging FC states during rest in 51 antidepressant-free MDD patients at high risk of recurrence (≥2 previous episodes), and 35 healthy controls. We examined differences in occurrence, duration, and switching profiles of FC states after neutral and sad mood induction. Remitted MDD patients showed a decreased probability of an FC state (p < 0.005) consisting of an extensive network connecting frontal areas-important for cognitive control-with default mode network, striatum, and salience areas, involved in emotional and self-referential processing. Even when this FC state was observed in patients, it lasted shorter (p < 0.005) and was less likely to switch to a smaller prefrontal-striatum network (p < 0.005). Differences between patients and controls decreased after sad mood induction. Further, the duration of this FC state increased in remitted patients after sad mood induction but not in controls (p < 0.05). Our findings suggest reduced ability of remitted-MDD patients, in neutral mood, to access a clinically relevant control network involved in the interplay between externally and internally oriented attention. When recovering from sad mood, remitted recurrent MDD appears to employ a compensatory mechanism to access this FC state. This study provides a novel neurobiological profile of MDD vulnerability., (© 2019 The Authors. Human Brain Mapping published by Wiley Periodicals, Inc.)

An interesting factor explaining recurrence risk in Major Depressive Disorder (MDD) may be neuropsychological functioning, i.e., processing of emotional stimuli/information. Negatively biased processing of emotional stimuli/information has been found in both acute and (inconclusively) remitted states of MDD, and may be causally related to recurrence of depression. We aimed to investigate self-referent, memory and interpretation biases in recurrently depressed patients in remission and relate these biases to recurrence. We included 69 remitted recurrent MDD-patients (rrMDD-patients), 35-65 years, with ≥2 episodes, voluntarily free of antidepressant maintenance therapy for at least 4 weeks. We tested self-referent biases with an emotional categorization task, bias in emotional memory by free recall of the emotion categorization task 15 min after completing it, and interpretation bias with a facial expression recognition task. We compared these participants with 43 never-depressed controls matched for age, sex and intelligence. We followed the rrMDD-patients for 2.5 years and assessed recurrent depressive episodes by structured interview. The rrMDD-patients showed biases toward emotionally negative stimuli, faster responses to negative self-relevant characteristics in the emotional categorization, better recognition of sad faces, worse recognition of neutral faces with more misclassifications as angry or disgusting faces and less misclassifications as neutral faces (0.001 < p < 0.05). Of these, the number of misclassifications as angry and the overall performance in the emotional memory task were significantly associated with the time to recurrence ( p ≤ 0.04), independent of residual symptoms and number of previous episodes. In a support vector machine data-driven model, prediction of recurrence-status could best be achieved (relative to observed recurrence-rate) with demographic and childhood adversity parameters (accuracy 78.1%; 1-sided p = 0.002); neuropsychological tests could not improve this prediction. Our data suggests a persisting (mood-incongruent) emotional bias when patients with recurrent depression are in remission. Moreover, these persisting biases might be mechanistically important for recurrence and prevention thereof.

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., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Objectives: Cognitive reactivity (CR) to sad mood is a risk factor for major depressive disorder (MDD). CR is usually measured by assessing change on the Dysfunctional Attitudes Scale (DAS-change) after sad mood-induction. It has, however, been suggested that the versions of the DAS (A/B) are not interchangeable, impacting the reliability and validity of the change score. The Leiden Index of Depression Sensitivity-Revised (LEIDS-R) is an alternative self-report measure of CR. Studies examining the relationship between LEIDS-R and DAS-change have shown mixed results. We examined whether scores of these CR measures differed between remitted MDD and controls, the relationship between these CR measures, and the effect of order of DAS administration on DAS-change., Design: Cross-sectional design with two groups (remitted MDD and controls)., Methods: Sixty-eight MDD patients remitted from ≥2 previous episodes, not taking antidepressants, and 43 never-depressed controls participated in a mood-induction and filled in the DAS-A/B in randomized order before and after mood-induction, and LEIDS-R separately., Results: LEIDS-R scores and pre-mood-induction DAS scores were significantly higher in remitted MDD than controls (p < .001, Cohen's d = 1.48; p = .001, Cohen's d = 0.66, respectively). DAS-change did not differ between these groups (p = .67, Cohen's d = 0.08). LEIDS-R correlated with DAS-change (r = .30, p = .042), but only in the group that filled in DAS-B before DAS-A. In remitted MDD, DAS-change was dependent on the order of DAS versions before and after mood-induction (10.6 ± 19.0 vs. -1.2 ± 10.5, for order B-A and A-B, respectively), with a significant group × order interaction (p = .012)., Conclusions: Existing DAS versions are not interchangeable, which compromises the usefulness of mood-inductions in clinical practice. The LEIDS-R seems a valid measure of cognitive vulnerability to depression., Practitioner Points: Clinical implications: Cognitive reactivity (CR) is a risk factor of depressive recurrence. The current measurement of CR, by assessing change on the Dysfunctional Attitudes Scale (DAS) after mood-induction, is not reliable. The Leiden Index Depression Sensitivity-Revised (LEIDS-R) is an alternative CR measure. In contrast to mood-induction, it reliably assesses depression vulnerability. The use of mood-inductions for clinical/research purposes is unnecessary., Limitations of the Study: We were not able to examine the effect of previous treatment, which could have affected results as psychological treatments probably have differential effects on CR. Examining un-medicated patients may have led to selection of a sample not completely representative for the general MDD population. We did not administer both parallel versions of the DAS (A/B) before and after mood-induction. This might have provided better understanding of their differential sensitivity to change., (© 2018 The Authors. British Journal of Clinical Psychology published by John Wiley & Sons Ltd on behalf of British Psychological Society.)

Continuous research into the pathophysiology of psychiatric disorders, such as major depressive disorder (MDD), posttraumatic stress disorder (PTSD), and schizophrenia, suggests an important role for metabolism. This narrative review will provide an up-to-date summary of how metabolism is thought to be involved in the pathophysiology of these psychiatric disorders. We will focus on (I) the important role of fatty acids in these metabolic alterations, (II) whether fatty acid alterations represent epiphenomena or risk factors, and (III) similarities and dissociations in fatty acid alterations between different psychiatric disorders. (Historical) epidemiological evidence links fatty acid intake to psychiatric disorder prevalence, corroborated by altered fatty acid concentrations measured in psychiatric patients. These fatty acid alterations are connected with other concomitant pathophysiological mechanisms, including biological stress (hypothalamic-pituitary-adrenal (HPA)-axis and oxidative stress), inflammation, and brain network structure and function. Metabolomics and lipidomics studies are underway to more deeply investigate this complex network of associated neurometabolic alterations. Supplementation of fatty acids as disease-modifying nutraceuticals has clinical potential, particularly add-on eicosapentaenoic acid (EPA) in depressed patients with markers of increased inflammation. However, by interpreting the observed fatty acid alterations as partly (mal)adaptive phenomena, we attempt to nuance translational expectations and provide new clinical applications for these novel neurometabolic insights, e.g., to predict treatment response or depression recurrence. In conclusion, placing fatty acids in context can contribute to further understanding and optimized treatment of psychiatric disorders, in order to diminish their overwhelming burden of disease.

Genetic variations in the mu-opioid receptor (OPRM1) gene have been related to high sensitivity to rewarding effects of alcohol. The current study focuses on the neural circuitry underlying this phenomenon using an alcohol versus water taste-cue reactivity paradigm in a young sample at relatively early stages of alcohol use, thus limiting the confound of variations in duration of alcohol use. Drinkers (17-21 years old) were selected on genotype carrying the AA-(n = 20) or the AG-(n = 16) variant of the A118G single nucleotide polymorphism (SNP) of the OPRM1 gene (rs1799971), and underwent functional magnetic resonance imaging (fMRI). Magnitude of the neural activity and frontostriatal functional connectivity in response to alcohol versus water were investigated. The AG-group demonstrated reduced activation in prefrontal and parietal regions, including the inferior and middle frontal gyrus, superior and inferior parietal lobule, compared with the AA-group. No activation differences were observed in the mesolimbic pathway. Connectivity from the ventral-striatum to frontal regions for alcohol > water trials was higher in the AG than the AA group. For the dorsal-striatum seed region, the AG group showed increased connectivity to non-PFC regions. These results indicate that adolescents carrying the G-allele may be more vulnerable for the alcohol to hijack the reward system in the absence of frontal control to regulate craving. This implies that findings of hyperactivation in the mesolimbic structures of G-allele carriers in earlier studies might result from both genetic susceptibility and heavy drinking., (© 2016 Society for the Study of Addiction.)

Rumination and cognitive reactivity (dysfunctional cognitions after sad mood-induction) remain high in remitted Major Depressive Disorder (MDD) and can contribute to new episodes. These factors have been linked to increased fMRI resting-state functional-connectivity within the Default-Mode Network (DMN). It remains unclear whether (I) increased DMN-connectivity persists during MDD-remission, and (II) whether sad mood-induction differentially affects DMN-connectivity in remitted-MDD vs controls. Moreover, DMN-connectivity studies in remitted-MDD were previously confounded by antidepressant-use. Sixty-two MDD-patients remitted from ≥2 episodes, psychotropic-medication free, and 41 controls, participated in two 5-min neutral and sad mood-inductions by autobiographical-recall and neutral/sad music, each followed by 8-min resting-state fMRI-scanning. We identified DMN-components using Independent Component Analysis and entered subject- and sessions-specific components into a repeated measures analysis of variance. Connectivity-differences were extracted and correlated with baseline cognitive reactivity and rumination as measures of vulnerability for recurrence. After sad vs neutral mood-induction, controls, but not remitted-MDD, showed an increase in connectivity between the posterior-DMN and a cluster consisting mostly of the hippocampus (P = 0.006). Less posterior-DMN-hippocampal connectivity was associated with higher cognitive reactivity (r = -0.21, P = 0.046) and rumination (r = -0.27, P = 0.017). After recalling sad autobiographical-memories, aberrant posterior-DMN-hippocampal connectivity, associated with cognitive reactivity and rumination, remains a neural vulnerability in MDD-remission., (© The Author (2017). Published by Oxford University Press.)

Background/objectives: To investigate the association of dietary patterns derived by reduced rank regression (RRR) with depressive symptoms in a multi-ethnic population., Subjects/methods: Cross-sectional data from the HELIUS study were used. In total, 4967 men and women (18-70 years) of Dutch, South-Asian Surinamese, African Surinamese, Turkish and Moroccan origin living in the Netherlands were included. Diet was measured using ethnic-specific food frequency questionnaires. Depressive symptoms were measured with the nine-item patient health questionnaire., Results: By performing RRR in the whole population and per ethnic group, comparable dietary patterns were identified and therefore the dietary pattern for the whole population was used for subsequent analyses. We identified a dietary pattern that was strongly related to eicosapentaenoic acid+docosahexaenoic acid, folate, magnesium and zinc (response variables) and which was characterized by milk products, cheese, whole grains, vegetables, legumes, nuts, potatoes and red meat. After adjustment for confounders, a statistically significant inverse association was observed in the whole population (B: -0.03, 95% CI: -0.06, -0.00, P=0.046) and among Moroccan (B: -0.09, 95% CI: -0.13, -0.04, P=0.027) and South-Asian Surinamese participants (B: -0.05, 95% CI: -0.09, -0.01, P=<0.001), whereas no statistically significant association was found in the remaining ethnic groups. No statistically significant associations were found between the dietary pattern and significant depressed mood in any of the ethnic groups., Conclusions: No consistent evidence was found that consumption of a dietary pattern, high in nutrients that are hypothesized to protect against depression, was associated with lower depressive symptoms across different ethnic groups.

Background: A better understanding of factors underlying antidepressant non-response may improve the prediction of which patients will respond to what treatment. Major depressive disorder (MDD) is associated with alterations in fatty acid metabolism, (neuro)inflammation and amygdala-reactivity. However, their mutual relations, and the extent to which they are associated with prospective antidepressant-response, remain unknown., Purpose: To test (I) alterations in (neuro)inflammation and its associations with fatty acid metabolism and amygdala-reactivity in MDD-patients compared to controls, and (II) whether these alterations are associated with prospective paroxetine response., Methods: We compared 70 unmedicated MDD-patients with 51 matched healthy controls at baseline, regarding erythrocyte membrane omega-6 arachidonic acid (AA), inflammation [serum (high-sensitivity) C-reactive protein (CRP)], and in a subgroup amygdala-reactivity to emotional faces using functional magnetic resonance imaging (fMRI) (N=42). Subsequently, we treated patients with 12 weeks paroxetine, and repeated baseline measures after 6 and 12 weeks to compare non-responders, early-responders (response at 6 weeks), and late-responders (response at 12 weeks)., Results: Compared to controls, MDD-patients showed higher CRP (p=0.016) and AA (p=0.019) after adjustment for confounders at baseline. AA and CRP were mutually correlated (p=0.043). In addition, patients showed a more negative relation between AA and left amygdala-reactivity (p=0.014). Moreover, AA and CRP were associated with antidepressant-response: early responders showed lower AA (p=0.018) and higher CRP-concentrations (p=0.008) than non-responders throughout the study., Conclusion: Higher observed CRP and AA, their mutual association, and relation with amygdala-reactivity, are corroborative with a role for (neuro)inflammation in MDD. In addition, observed associations of these factors with prospective antidepressant-response suggest a potential role as biomarkers. Future studies in independent samples are needed to replicate and test the clinical applicability of these biological predictors for treatment response to result in a precision/personalized medicine approach for treatment., (Copyright © 2017 Elsevier Ltd. All rights reserved.)