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

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

Good practice in mental health care for socially marginalised groups in Europe: a qualitative study of expert views in 14 countries

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Negative cognitive schema modification as mediator of symptom improvement after electroconvulsive therapy in major depressive disorder

Background: Electroconvulsive therapy (ECT) is a potent option for treatment-resistant major depressive disorder (MDD). Cognitive models of depression posit that negative cognitions and underlying all-or-nothing negative schemas contribute to and perpetuate depressed mood. This study investigates whether ECT can modify negative schemas, potentially via memory reactivation, and whether such changes are related to MDD symptom improvement. Method: Seventy-two patients were randomized to either an emotional memory reactivation electroconvulsive therapy (EMR-ECT) or control memory reactivation electroconvulsive therapy (CMR-ECT) intervention prior to ECT-sessions in a randomized controlled trail. Emotional memories associated with patients' depression were reactivated before ECT-sessions. At baseline and after the ECT-course, negative schemas and depression severity were assessed using the Dysfunctional Attitude Scale (DAS) and Hamilton Depression Rating Scale HDRS. Mediation analyses were used to examine whether the effects of ECT on HDRS-scores were mediated by changes in DAS-scores or vice versa. Results: Post-ECT DAS-scores were significantly lower compared to baseline. Post-ECT, the mean HDRS-score of the whole sample (15.10 ± 8.65 [SD]; n = 59) was lower compared to baseline (24.83 ± 5.91 [SD]). Multiple regression analysis showed no significant influence of memory reactivation on schema improvement. Path analysis showed that depression improvement was mediated by improvement of negative cognitive schemas. Conclusion: ECT is associated with improvement of negative schemas, which appears to mediate the improvement of depressive symptoms. An emotional memory intervention aimed to modify negative schemas showed no additional effect

Effectiveness of Emotional Memory Reactivation vs Control Memory Reactivation Before Electroconvulsive Therapy in Adult Patients With Depressive Disorder A Randomized Clinical Trial:A Randomized Clinical Trial

Importance: Although electroconvulsive therapy (ECT) is often effective, approximately half of patients with depression undergoing ECT do not benefit sufficiently, and relapse rates are high. ECT sessions have been shown to weaken reactivated memories. The effect of emotional memory retrieval on cognitive schemas remains unknown. Objective: To assess whether emotional memory retrieval just before patients receive ECT sessions weakens underlying cognitive schemas, improves ECT effectiveness, increases ECT response, and reduces relapse rates. Design, Setting, and Participants: In this multicenter randomized clinical trial conducted from 2014 to 2018 in the departments of psychiatry in 3 hospitals in the Netherlands, 72 participants were randomized 1:1 to 2 parallel groups to receive either emotional memory reactivation (EMR-ECT) or control memory reactivation (CMR-ECT) interventions before ECT sessions. The Hamilton Depression Rating Scale (HDRS [total score range: 0-52, with 0-7 indicating no depression and ≥24 indicating severe depression]) was used to measure symptoms of depression during and after ECT, with a 6-month follow-up period. Participants were between ages 18 and 70 years with a primary diagnosis of unipolar major depressive disorder (MDD) according to the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition, Text Revision) and in whom ECT was indicated. Data analysis was performed from July to November 2019. Interventions: EMR-ECT or CMR-ECT interventions prior to ECT sessions. Main Outcomes and Measures: Depression scores and relapse rates within 6 months were assessed with the HDRS and analyzed using logistic and linear multiple regression analyses. Results: A total of 66 patients (mean [SD] age, 49.3 [12.3] years; 39 [59.1%] women) were randomized to the EMR-ECT group (n = 32) or the CMR-ECT group (n = 34). Regardless of the memory intervention, 42.4% (28 of 66) of patients responded (≥50% decrease of symptom severity on the HDRS). Of patients who responded, 39.3% (11 of 28) relapsed within 6 months. Remission rates (CMR-ECT group, 29.4% [10 of 34] vs EMR-ECT group, 25.0% [8 of 32]; P = .58), mean (SD) HDRS scores after the ECT course (CMR-ECT group, 14.6 [8.6] vs EMR-ECT group, 14.9 [8.8]; P = .88), total mean (SD) number of required ECT sessions for response (CMR-ECT group, 14.9 [7.9] vs EMR-ECT group, 15.6 [7.3]; P = .39), and relapse rates (CMR-ECT group, 46.7% [7 of 15] vs EMR-ECT group, 30.8% [4 of 13]; P = .33) were not significantly altered by the intervention. Conclusions and Relevance: Study findings suggest that the EMR-ECT intervention just before patient receipt of ECT for depression did not improve effectiveness, increase speed of response, or reduce relapse rates after the ECT course compared with patients receiving CMR-ECT. Trial Registration: Trialregister.nl Identifier: NL4289

Meta-analysis and meta-regression of omega-3 polyunsaturated fatty acid supplementation for major depressive disorder

Contains fulltext : 167940.pdf (publisher's version ) (Open Access)Omega-3 polyunsaturated fatty acid (PUFA) supplementation has been proposed as (adjuvant) treatment for major depressive disorder (MDD). In the present meta-analysis, we pooled randomized placebo-controlled trials assessing the effects of omega-3 PUFA supplementation on depressive symptoms in MDD. Moreover, we performed meta-regression to test whether supplementation effects depended on eicosapentaenoic acid (EPA) or docosahexaenoic acid dose, their ratio, study duration, participants' age, percentage antidepressant users, baseline MDD symptom severity, publication year and study quality. To limit heterogeneity, we only included studies in adult patients with MDD assessed using standardized clinical interviews, and excluded studies that specifically studied perinatal/perimenopausal or comorbid MDD. Our PubMED/EMBASE search resulted in 1955 articles, from which we included 13 studies providing 1233 participants. After taking potential publication bias into account, meta-analysis showed an overall beneficial effect of omega-3 PUFAs on depressive symptoms in MDD (standardized mean difference=0.398 (0.114-0.682), P=0.006, random-effects model). As an explanation for significant heterogeneity (I(2)=73.36, P<0.001), meta-regression showed that higher EPA dose (beta=0.00037 (0.00009-0.00065), P=0.009), higher percentage antidepressant users (beta=0.0058 (0.00017-0.01144), P=0.044) and earlier publication year (beta=-0.0735 (-0.143 to 0.004), P=0.04) were significantly associated with better outcome for PUFA supplementation. Additional sensitivity analyses were performed. In conclusion, present meta-analysis suggested a beneficial overall effect of omega-3 PUFA supplementation in MDD patients, especially for higher doses of EPA and in participants taking antidepressants. Future precision medicine trials should establish whether possible interactions between EPA and antidepressants could provide targets to improve antidepressant response and its prediction. Furthermore, potential long-term biochemical side effects of high-dosed add-on EPA supplementation should be carefully monitored

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

The endorsement of dysfunctional attitudes is associated with an impaired retrieval of specific autobiographical memories in response to matching cues

Two studies investigated a hypothesis of Dalgleish et al. (2003) that overgeneral memory may arise from matching between task cues and dysfunctional attitudes or schemas. In the first study, 111 euthymic patients with at least two previous major depressive episodes completed the Dysfunctional Attitude Scale: Form A (DAS-A) and the Autobiographical Memory Test (AMT). In the second study, 82 patients with a borderline personality disorder completed the Young Schema Questionnaire (YSQ) and the same version of the AMT. In both studies, patients retrieved less specific autobiographical memories in response to cue words that matched highly endorsed attitudes or schemas. These results suggest that an impaired retrieval of specific memories may be the result of certain cues activating generic, higher-order mental representations