A prediction model for electroconvulsive therapy effectiveness in patients with major depressive disorder from the Dutch ECT Consortium (DEC).

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.

The sensitivity of the Mini-Mental State Examination to detect objective cognitive side-effects induced by electroconvulsive therapy, results from the Dutch ECT Consortium.

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.

Depression recurrence is accompanied by longer periods in default mode and more frequent attentional and reward processing dynamic brain-states during resting-state activity.

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.

The relationship between cognitive functioning and psychopathology in patients with psychiatric disorders: a transdiagnostic network analysis.

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.

Tractography-based versus anatomical landmark-based targeting in vALIC deep brain stimulation for refractory obsessive-compulsive disorder.

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 (BF10 = 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; BF10 = 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.

Suicidal ideation in remitted major depressive disorder predicts recurrence.

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 HDRS17 and IDS-SR30 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) (χ2 = 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 (χ2 = 7.26, p < .026). Higher suicidal symptoms were longitudinally related to higher depressive symptoms (HDRS17; F = 49.87, p < .001), IDS-SR30; (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.

Why Has Deep Brain Stimulation Had So Little Impact in Psychiatry?

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.

Predicting Response to vALIC Deep Brain Stimulation for Refractory Obsessive-Compulsive Disorder.

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, χ21 = 5.259, P = .022). Late-onset OCD was associated with more symptom decrease (ß = -0.29; 95% CI, -0.53 to -0.04; P = .023) and comorbid personality disorder with less symptom decrease over time (ß = 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.

Marine Omega-3 Fatty Acid Supplementation for Borderline Personality Disorder: A Meta-Analysis.

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 (I2 = 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.

Invasive and Non-invasive Neurostimulation for OCD.

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.

Metabolic features of recurrent major depressive disorder in remission, and the risk of future recurrence.

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.

Omega-3 Fatty Acid Supplementation for Perinatal Depression: A Meta-Analysis.

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.

Protocol Across study: longitudinal transdiagnostic cognitive functioning, psychiatric symptoms, and biological parameters in patients with a psychiatric disorder.

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.

Impaired reward-related learning signals in remitted unmedicated patients with recurrent depression.

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.

Attentional control, rumination and recurrence of depression.

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, (HRSD) = 0.563 [CI, 0.381-0.832], p = 0.004, (HRSD) = 0.561 [CI, 0.389-0.808], p = 0.002, respectively). Rumination predicted recurrence (HRSD = 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.

Emotional Biases and Recurrence in Major Depressive Disorder. Results of 2.5 Years Follow-Up of Drug-Free Cohort Vulnerable for Recurrence.

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.

Altered ability to access a clinically relevant control network in patients remitted from major depressive disorder.

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.