Deep brain stimulation (DBS) is a neurosurgical intervention for severe, treatment-refractory obsessive-compulsive disorder (OCD). Here, we conducted the first meta-analysis using individual participant outcome data, comparing DBS to sham-stimulation in randomized controlled trials (RCTs), and systematically evaluated adverse events and methodological trial quality. We conducted a comprehensive systematic search in multiple databases and included randomized-controlled trials comparing DBS with sham in adult patients with OCD. We obtained YBOCS data for individual participants and performed a two-stage random-effects meta-analysis. Nine RCTs with small sample sizes were included, resulting in a total sample of 91 patients. Meta-analysis of showed a decrease of 5.1 YBOCS points in favor of DBS compared to sham (95% confidence interval (CI) 2.3 – 7.9, 0.56 Hedges’ g). OR was 5.7, 95% CI 2.2 - 15), with a NNT of 3.3. Efficacy of studies that optimized DBS parameters was much higher than that of non-optimized studies (beta 5.1, 95% CI 0.59 – 9.5, p-value 0.026). Adverse events occurred during surgery, active and sham trial phases, and follow-up, with hypomania and cognitive problems being the most frequently reported stimulation-related adverse events. Concluding, we found a significant effect of DBS compared to sham in treating OCD, especially after DBS parameter optimization. However, the quality of evidence was low, and heterogeneity was high. More rigorous sham-controlled evidence could further improve credibility of DBS for OCD. PROSPERO-registration number: CRD42024546836

Background Schizophrenia is a heterogeneous disorder. Conflicting findings concerning abnormal levels of red blood cell fatty acids (RBC FA) in schizophrenia patients compared to healthy controls have been found. This stimulated research on the possible presence of a bimodal distribution of RBC FA. Bimodality suggests subgroups of the disease, including different endophenotypes and/or clinical characteristics. However, to date only a small number of publications reported on bimodality. The evidence whether fatty acids in red blood cells are bimodally distributed in schizophrenia is conflicting and data on bimodality in healthy controls are limited. The aim of current study was to investigate whether bimodal distributions of RBC FA concentrations are present in stable patients as compared to controls, and if so whether these distributions differ in form or size between patients and healthy controls. Methods From the GROUP study, a multisite, longitudinal, naturalistic cohort study, we investigated a subset of 215 patients, between 16 and 50 years, with a psychotic disorder and 98 healthy controls, between 16 and 50 years, for which RBC FA measurements were available. We studied a panel of 28 RBC FAs; 7 saturated fatty acids (SFAs), 9 monounsaturated fatty acids (MUFAs) and 12 polyunsaturated fatty acids (PUFAs). We did not investigate underlying genetics. The Likelihood Ratio Test was used to compare the goodness of fit of a bimodal or a unimodal distribution of each of the 28 FA concentrations. Hierarchical regressions were used to investigate whether belonging to the lower end of the distribution was associated with higher positive or negative symptom severity. Results At baseline, 19 out of 28 FAs are significantly bimodally distributed in patients versus 11 out of 28 FAs in controls (p < .05). As a group, RBC FAs in patients are borderline significant more often bimodally distributed as compared to controls. In contrast to previous studies, for AA, DHA and EPA we did not find a bimodal distribution in patients and an unimodal distribution in controls. Belonging to the lower end of the RBC FA distribution was not associated with positive or negative symptom severity. Conclusions Our findings do not support the existence of a unique bimodality of RBC FA distribution in relatively stable patients with schizophrenia spectrum disorders compared to controls. Bimodality may be more pronounced in the acute phase of the disease, further research into bimodality should focus on the influence of oxidative stress on levels of FAs and bimodality in (partly) remitted patients as well as acutely ill patients.

Deep brain stimulation (DBS) reduces depressive symptom scores in many patients with treatment-resistant depression (TRD). However, it is unclear whether the observed improvement is similar across various symptom dimensions (e.g., anhedonia, anxiety, insomnia) or if some require additional clinical attention. Using a retrospective chart review, we assessed the trajectory of HAM-D-17 and MADRS scores during vALIC or slMFB DBS treatment within different symptom dimensions (HAM-D-17: 1) affective/anhedonia, 2) somatic/anxiety, 3) insomnia; MADRS: 1) affective/anhedonia, 2) anxiety/vegetative, 3) hopelessness) after at least a 25 ​% symptom reduction (partial response) at any time during their treatment course (n ​= ​34 for HAM-D-17, n ​= ​25 for MADRS). Results showed that each of the assessed symptom dimensions was significantly reduced compared to baseline at each of the assessed time periods (last follow-up: 2-15 years) after (partial) DBS response onset, which occurred at a median of approximately 2.5 months. Additionally, there was a significant interaction effect between symptom dimension and time period (HAM-D-17: F (12,1655.46) ​= ​5.46, p ​< ​0.001; MADRS: F (12,938.73) ​= ​2.40, p ​< ​0.01). Model coefficients indicated that insomnia symptoms (HAM-D-17) and anxiety/vegetative symptoms (MADRS) improved at a slower rate than the other symptom dimensions. Additionally, higher baseline scores in the HAM-D-17 somatic/anxiety dimension were significantly associated with a larger percentage reduction in overall symptoms after DBS (n ​= ​39, F (1,32) ​= ​12.371, p ​< ​0.01). Our findings demonstrate that DBS for TRD effectively treats depressive symptoms in all dimensions, although insomnia symptoms may improve at a slower rate, and that patients with more anxiety symptoms, who typically tend to have worse pharmacological treatment outcomes, may particularly benefit from DBS.

Introduction Deep brain stimulation (DBS) has become an established therapy for otherwise treatment-refractory obsessive-compulsive disorder (OCD). Although several studies and meta-analyses have demonstrated its efficacy, the results thus far have not been analyzed with the novel tool of an umbrella review. Here, we aim to provide an umbrella review and an updated meta-analysis of all previously published data concerning the outcomes of DBS for OCD. Methods In adherence to PRISMA guidelines, an umbrella review and meta-analysis was conducted, systematically searching PubMed, Medline, Embase, and Web of Science for meta-analyses on the treatment of OCD with DBS. Individual studies within the included meta-analyses, along with new studies, were meticulously reviewed, and duplications were removed. The results were collected and pooled to generate forest plots. The primary outcome was the relative change in Y-BOCS, HAM-A, HAM-D and Global Assessment of Functioning (GAF) scores at the last available follow-up after DBS. Results This umbrella review encompassed seven meta-analyses evaluating the outcomes of DBS in patients with OCD published between 2014 and 2022. The current updated meta-analysis, including 29 studies, revealed significant overall improvement in OCD symptoms following DBS, as measured by Y-BOCS (mean difference (MD = 14.12 95 %CI = 12.43, 15.82, p < 0.00001, I² = 73 %), HAM-A (MD = 10.71, 95 %CI = 8.55, 12.88, p < 0.00001, I² = 63 %), HAM-D (MD = 11.14, 95 %CI = 9.39, 12.89, p < 0.00001, I² = 0 %), and GAF scales (MD = 5.20, 95 %CI = 4.51, 5.89, p < 0.00001, I² = 99 %). Conclusion Our advanced analysis confirms that DBS is an effective therapy for OCD and its associated co-morbidities. Further research is essential to better understand and assess treatment efficacy and its underlying mechanisms.

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&rsquo; 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.

The evidence on the techniques, targets, and clinical results of deep brain stimulation (DBS) in obsessive-compulsive disorder (OCD) is constantly evolving. The aim of this chapter is to provide an overview of the latest updates on clinical results of DBS in OCD, predictors of response, and the mechanisms of action. Overall, studies have shown a significant mean improvement in Yale-Brown Obsessive Compulsive Scale of approximately 47% (95% CI 40%–53%) across treatment-refractory OCD patients. Furthermore, the quality of life improved in the physical and psychological domains at all targets. Surgery-related serious adverse events (SAEs) are relatively rare (7.9%) and mostly transient. These include infection and intracranial hemorrhage. In order to improve implementation of DBS in clinical practice for treatment of OCD and psychiatric disorders in general, it is important to educate future clinicians about the effectiveness of DBS in OCD.

BACKGROUND:Monitoring cognitive side effects following electroconvulsive therapy (ECT) is crucial for balancing side effects and clinical effectiveness. Yet, 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 score and its performance in identifying a decline in predefined neuropsychological measures sensitive to ECT-induced cognitive changes: verbal recall and verbal fluency. METHODS:Mean MMSE scores before and 1 week after ECT were compared using a Wilcoxon signed rank test. The Reliable Change Index was calculated for all cognitive measures to indicate whether a participant's change in score from pre- to post-ECT was considered statistically significant. The sensitivity and specificity of the MMSE were calculated. RESULTS:A total of 426 patients with depression from 5 sites were included from the Dutch ECT Consortium. Mean (SD) MMSE score increased significantly from 26.2 (3.9) before ECT to 26.8 (3.8) after ECT (p = .002). After ECT, 36 patients (8.5%) showed a significant decline in MMSE score. 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.

Existential concerns, such as autonomy and identity, are often overlooked although they play an important role in psychopathology and clinical practice. The aims of this study are to investigate how existential concerns relate to psychopathological symptoms and to identify important existential concerns. This study used a cross-sectional quantitative design with a transdiagnostic sample. A mixed graphical model of 4 existential and 3 symptom domains with 4 covariates was estimated in a sample of 996 individuals with various psychiatric disorders. Symptom nodes were derived from questionnaires on psychopathological symptoms and existential nodes from questionnaires on transdiagnostic psychiatric dimensions and self-esteem. The centrality metric, expected influence, was calculated to determine nodes’ cumulative influence in the network. Existential concerns were related to worse psychopathology overall, but most strongly to depressive and anxiety symptoms. The strongest cross-domain relationship was between anxiety and recognition of psychiatric disorder. Of the existential concerns, autonomy and identity were the most central nodes in the network. Our results advocate the need to address existential concerns in clinical practice and research. Conveying individual responses to experiencing psychopathology, such as recognition of disorder, and supporting autonomy or positive identity formation may be areas for intervention.

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. 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. 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. 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). Anorexia Nervosa (An) is a severe eating disorder with many, sometimes life-threatening, complications. A substantial number of AN patients do not respond to the available treatment options and remain chronically ill or even die as a consequence of the AN. Because part of the causes of AN may reside in the brain, we studied the efficacy and safety of a potential new treatment option for AN, namely deep brain stimulation (DBS). DBS has proven to be an effective treatment option for movements disorders like Parkinson’s Disease and other psychiatric disorders such as obsessive compulsive disorder. Our previous pilot study and other research have shown that DBS leads to improvements in weight, mood, anxiety, and eating disorder symptoms. In this substudy, we examined the effects of DBS on specific brain circuitries that are implicated in AN. We conducted brain scans (fMRI) to measure brain activity while patients performed tasks. We observed a difference in brain response when we compared scans taken before and after the DBS, which supports our thoughts on the involvement of specific parts of the brain in AN.

Background: Deep brain stimulation (DBS) of the ventral anterior limb of the internal capsule (vALIC) is effective for refractory obsessive-compulsive disorder (OCD), but patients typically require high stimulation voltages and DBS comes with a risk for adverse events (AE). Objective: The aim of the present study was to advance DBS for OCD by optimizing energy efficiency and minimize adverse events using a cyclic form of stimulation Methods: This double blind, randomized crossover trial compares 2 weeks of continuous versus cyclic DBS (0.1 s ON, 0.2 s OFF) in 16 patients with OCD. We compared OCD symptoms (Yale-Brown Obsessive-Compulsive Scale, Y-BOCS), Hamilton Depression Rating Scale (HAM-D), Hamilton Anxiety Scale (HAM-A), AEs, battery life, cognitive performance and quality of life. Results: Average Y-BOCS scores at baseline increased significantly with 5.5 points (p = 0.006) in the cyclic condition. Average HAM-D and HAM-A scores increased with 2.2 (p = 0.088) and 2.8 points (p = 0.018). The overall health scale of quality of life worsened during cyclic DBS (p = 0.044). Patients reported on average 3.3 AEs during continuous stimulation and 4.4 AEs during cyclic stimulation (p = 0.175), though stimulation-related AEs such as headache and concentration problems reduced during cyclic DBS. Battery usage during continuous DBS was 0.021 V per hour compared to 0.008 V per hour during cyclic DBS. Conclusion: Though specific stimulation-related AEs improved, cyclic stimulation (0.1 s ON, 0.2 s OFF) comes with a high relapse risk in patients with DBS for OCD. Cyclic DBS is no alternative for standard DBS treatment, but applicable in case of debilitating AEs.

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.

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.

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.

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.

Empirical evidence and clinical observations suggest a strong -yet under acknowledged-link between anorexia nervosa (AN) and non-suicidal self-injurious behavior (NSSI). By reviewing the literature on the psychopathology and neurobiology of AN and NSSI, we shed light on their relationship. Both AN and NSSI are characterized by disturbances in affect regulation, dysregulation of the reward circuitry and the opioid system. By formulating a reward-centered hypothesis, we explain the overlap between AN and NSSI. We propose three approaches understanding the relationship between AN and NSSI, which integrate psychopathology and neurobiology from the perspective of self-destructiveness: (1) a nosographical approach, (2) a research domain (RDoC) approach and (3) a network analysis approach. These approaches will enhance our knowledge of the underlying neurobiological substrates and may provide groundwork for the development of new treatment options for disorders of self-destructiveness, like AN and NSSI. In conclusion, we hypothesize that self-destructiveness is a new, DSM-5-transcending concept or psychopathological entity that is reward-driven, and that both AN and NSSI could be conceptualized as disorders of self-destructiveness.

Objective: Several pioneering studies investigated deep brain stimulation (DBS) in treatment-refractory Anorexia Nervosa (AN) patients, but overall effects remain yet unclear. Aim of this study was to obtain estimates of efficacy of DBS in AN-patients using meta-analysis.Methods: We performed a literature search in MEDLINE, PsycInfo, and Embase, using terms related to DBS and AN. We included trials that investigated the clinical effects of DBS in AN-patients. We obtained data including psychiatric comorbidities, medication use, DBS target, and study duration. Primary outcome was Body Mass Index (BMI), secondary outcome was quality of life, and the severity of psychiatric symptoms, including eating disorder, obsessive-compulsive, depressive, and anxiety symptoms. The systematic review and meta-analysis protocol was registered in PROSPERO under study’s registration number: CRD42022295712.Findings: Four studies were included for meta-analysis, with a total of 56 patients with treatment-refractory AN. Follow-up ranged from 6-24 months. Random effects meta-analysis showed a significant increase in BMI following DBS, with a large effect size (Hedges’s g=1∙13; 95%CI=0∙80 to 1∙46; Z-value=6∙75; P<0∙001), without heterogeneity (I2=0∙00, P=0∙901). Random effects meta-analysis also showed a significant increase in quality of life (Hedges’s g=0∙86; 95%CI=0∙44 to 1∙28; Z-value=4∙01, P<0∙001). Furthermore, DBS decreased the severity of psychiatric symptoms (Hedges’s g=0∙89; 95%CI=0∙57 to 1∙21; Z-value=5∙47; P<0∙001, I2=4∙29, P=0∙371).Interpretation: In this first meta-analysis, DBS showed statistically large beneficial effects on weight restoration, quality of life, and reduction of psychiatric symptoms in patients with treatment-refractory AN. These outcomes call for more extensive naturalistic studies to determine the clinical relevance for functional recovery.Trial Registration Details: The systematic review and meta-analysis protocol was registered in PROSPERO under study’s registration number: CRD42022295712.Funding Information: Roel Mocking is supported by an unrestricted ABC talent grant.Declaration of Interests: The authors declare that they have no known competing financial interests that could have influenced the work reported in this meta-analysis.

Introduction Recurrence in major depression 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. Methods Sixty 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. Results After the transition into a depressive state, the reward and a 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 areas underlying the reward network were significantly less synchronized with the rest of the brain after recurrence (compared to a state of remission). These changes were not observed in the matched-remitted patients who were scanned twice while in remission. Conclusion These findings characterize the changes that are specifically associated with the transition from remission to recurrence and provide first evidence of increased segregation in the brain’s dynamical repertoire when a recurrent depressive episode occurs. ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Trial Netherlands Trial Register trial number: NTR3768 ### Clinical Protocols ### Funding Statement The DELTA-neuroimaging study was funded by the Dutch Brain Foundation [Hersenstichting; Grant #2009(2)-72]. Further support was obtained by unrestricted personal grants from the AMC to RJTM (AMC PhD Scholarship) and CAF (AMC MD-PhD Scholarship). HGR is supported by a NWO/ZonMW VENI-grant (#016.126.059). AT and NI are partly funded by the Dutch Brain Foundation [Hersenstichting; Grant #HA2015.01.07; SMARD]. RJTM is supported by an unrestricted ABC Talent Grant. MLK is supported by the Center for Music in the Brain, funded by the Danish National Research Foundation (DNRF117), and Centre for Eudaimonia and Human Flourishing at Linacre College funded by the Pettit and Carlsberg Foundations. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study was approved by the local Medical Ethical Committee of Amsterdam University Medical Centre. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes Data is available upon request via the Donders Repository (). Data can be provided by the Donders Institute for Brain, Cognition, and Behaviour pending scientific review and a completed data transfer agreement in collaboration with AmsterdamUMC. Requests for the data should be submitted to HR. The MATLAB scripts used to analyse the data in this study are publicly available at .