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 (I2=73.36, P<0.001), meta-regression showed that higher EPA dose (β=0.00037 (0.00009–0.00065), P=0.009), higher percentage antidepressant users (β=0.0058 (0.00017–0.01144), P=0.044) and earlier publication year (β=−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.

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.

ObjectiveCardiovascular disease (CVD) is the leading cause of death in severe psychiatric disorders (depression, schizophrenia). Here, we provide evidence of how the effects of oxidative stress on fatty acid (FA) and one-carbon (1-C) cycle metabolism, which may initially represent adaptive responses, might underlie comorbidity between CVD and psychiatric disorders.MethodWe conducted a literature search and integrated data in a narrative review.ResultsOxidative stress, mainly generated in mitochondria, is implicated in both psychiatric and cardiovascular pathophysiology. Oxidative stress affects the intrinsically linked FA and 1-C cycle metabolism: FAs decrease in chain length and unsaturation (particularly omega-3 polyunsaturated FAs), and lipid peroxidation products increase; the 1-C cycle shifts from the methylation to transsulfuration pathway (lower folate and higher homocysteine and antioxidant glutathione). Interestingly, corresponding alterations were reported in psychiatric disorders and CVD. Potential mechanisms through which FA and 1-C cycle metabolism may be involved in brain (neurocognition, mood regulation) and cardiovascular system functioning (inflammation, thrombosis) include membrane peroxidizability and fluidity, eicosanoid synthesis, neuroprotection and epigenetics.ConclusionWhile oxidative-stress-induced alterations in FA and 1-C metabolism may initially enhance oxidative stress resistance, persisting chronically, they may cause damage possibly underlying (co-occurrence of) psychiatric disorders and CVD. This might have implications for research into diagnosis and (preventive) treatment of (CVD in) psychiatric patients.

BackgroundThe polyunsaturated fatty acid (PUFA) composition of (nerve) cell membranes may be involved in the pathophysiology of depression. Studies so far, focussed mainly on omega-3 and omega-6 PUFAs. In the present study, saturated fatty acids (SFAs), monounsaturated fatty acids (MUFAs) and PUFAs of the omega-3, -6 and -9 series in plasma and erythrocytes of patients with recurrent major depressive disorder (MDD-R) were compared with controls.Methodology and Principal FindingsWe carried out a case-control study. The sample consisted of 137 patients with MDD-R and 65 matched non-depressed controls. In plasma and erythrocytes of patients with MDD-R the concentrations of most of the SFAs and MUFAs, and additionally erythrocyte PUFAs, all with a chain length >20 carbon (C) atoms, were significantly lower than in the controls. In contrast, the concentrations of most of the shorter chain members (≤18C) of the SFAs and MUFAs were significantly higher in the patients. Estimated activities of several elongases in plasma of patients were significantly altered, whereas delta-9 desaturase activity for C14∶0 and C18∶0 was significantly higher.Conclusions/SignificanceThe fatty acid status of patients with MDD-R not only differs with regard to omega-3 and omega-6 PUFAs, but also concerns other fatty acids. These alterations may be due to: differences in diet, changes in synthesizing enzyme activities, higher levels of chronic (oxidative) stress but may also result from adaptive strategies by providing protection against enhanced oxidative stress and production of free radicals.

Deep brain stimulation (DBS) is an effective treatment option for patients with refractory obsessivecompulsive disorder (OCD). However, clinical experience with DBS for OCD remains limited. The authors examined the tolerability and effectiveness of DBS in an open study of patients with refractory OCD.Methods: Seventy consecutive patients, including 16 patients from a previous trial, received bilateral DBS of the ventral anterior limb of the internal capsule (vALIC) between April 2005 and October 2017 and were followed for 12 months. Primary effectiveness was assessed by the change in scores on the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) from baseline until the 12-month follow-up. Response was defined by a $35% decrease in Y-BOCS score, partial response was defined by a 25%234% decrease, and nonresponse was defined by a ,25% decrease. Secondary effectiveness measures were the Hamilton Anxiety Rating Scale (HAM-A) and the Hamilton Depression Rating Scale (HAM-D).Results: Y-BOCS, HAM-A, and HAM-D scores all decreased significantly during the first 12 months of DBS. Twelve months of DBS resulted in a mean Y-BOCS score decrease of 13.5 points (SD=9.4) (40% reduction; effect size=1.5). HAM-A scores decreased by 13.4 points (SD=9.7) (55%; effect size= 1.4), and HAM-D scores decreased by 11.2 points (SD= 8.8) (54%; effect size=1.3). At the 12-month follow-up, 36 of the 70 patients were categorized as responders (52%), 12 patients as partial responders (17%), and 22 patients as nonresponders (31%). Adverse events included transient symptoms of hypomania, agitation, impulsivity, and sleeping disorders.Conclusions: These results confirm the effectiveness and safety of DBS of the vALIC for patients with treatmentrefractory OCD in a regular clinical setting.

Our results indicate that remitted recurrent MDD-patients have a persistent trait of increased cortisol concentrations, irrespective of stress. In combination with our finding that patients' cortisol concentrations do not change during new MDD-episodes (and thus not represent epiphenomenal or state-effects), our results support that hypercortisolemia fulfills the state-independence criterion for an endophenotype for recurrent depression.

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Defining reference models for population variation, and the ability to study individual deviations is essential for understanding inter-individual variability and its relation to the onset and progression of medical conditions. In this work, we assembled a reference cohort of neuroimaging data from 82 sites (N=58,836; ages 2-100) and use normative modeling to characterize lifespan trajectories of cortical thickness and subcortical volume. Models are validated against a manually quality checked subset (N=24,354) and we provide an interface for transferring to new data sources. We showcase the clinical value by applying the models to a transdiagnostic psychiatric sample (N=1,985), showing they can be used to quantify variability underlying multiple disorders whilst also refining case-control inferences. These models will be augmented with additional samples and imaging modalities as they become available. This provides a common reference platform to bind results from different studies and ultimately paves the way for personalized clinical decision making.