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.@en

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.@en

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.@en

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.@en

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.@en

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.@en

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.@en