A healthy dietary pattern is associated with microbiota diversity in recently diagnosed bipolar patients: The Bipolar Netherlands Cohort (BINCO) study.

BACKGROUND: Diet largely impacts the gut microbiota, and may affect mental and somatic health via the gut-brain axis. As such, the relationship between diet and the microbiota in Bipolar Disorder (BD) could be of importance, but has not been studied before. The aim was therefore to assess whether dietary quality is associated with the gut microbiota diversity in patients with recently diagnosed BD, and whether changes occur in dietary quality and microbiota diversity during their first year of treatment. METHODS: Seventy recently (<1 year) diagnosed patients with BD were included in the "Bipolar Netherlands Cohort" (BINCO), and a total of 45 participants were assessed after one year. A 203-item Food Frequency Questionnaire (FFQ) data yielded the Dutch Healthy index (DHD-15), and the microbiota composition and diversity of fecal samples were characterized by 16S rRNA gene amplicon sequencing at baseline and 1-year follow-up. Associations and changes over time were analyzed using multivariate regression analyses and t-tests for paired samples. RESULTS: Included patients had a mean age of 34.9 years (SD ± 11.2), and 58.6 % was female. Alpha diversity (Shannon diversity index), richness (Chao1 index) and evenness (Pielou's Evenness Index) were positively associated with the DHD-15 total score, after adjustment for sex, age and educational level (beta = 0.55; P < 0.001, beta = 0.39; P = 0.024, beta = 0.54; P = 0.001 respectively). The positive correlations were largely driven by the combined positive effect of fish, beans, fruits and nuts, and inverse correlations with alcohol and processed meats. No significant changes were found in DHD-15 total score, nor in microbiota diversity, richness and evenness indexes during one year follow-up and regular treatment. CONCLUSION: A healthy and varied diet is associated with the diversity of the microbiota in BD patients. Its potential consequences for maintaining mood stability and overall health should be studied further.

Dynamic reconfigurations of brain networks in depressive and anxiety disorders: The influence of antidepressants.

Major Depressive Disorder (MDD) and anxiety disorders are highly comorbid recurrent psychiatric disorders. Reduced dynamic reconfiguration of brain regions across subnetworks may play a critical role underlying these deficits, with indications of normalization after treatment with antidepressants. This study investigated dynamic reconfigurations in controls and individuals with a current MDD and/or anxiety disorder including antidepressant users and non-users in a large sample (N = 207) of adults. We quantified the number of subnetworks a region switched to (promiscuity) as well as the total number of switches (flexibility). Average whole-brain (i.e., global) values and subnetwork-specific values were compared between diagnosis and antidepressant groups. No differences in reconfiguration dynamics were found between individuals with a current MDD (N = 49), anxiety disorder (N = 46), comorbid MDD and anxiety disorder (N = 55), or controls (N = 57). Global and sensorimotor network (SMN) promiscuity and flexibility were higher in antidepressant users (N = 49, regardless of diagnosis) compared to non-users (N = 101) and controls. Dynamic reconfigurations were considerably higher in antidepressant users relative to non-users and controls, but not significantly altered in individuals with a MDD and/or anxiety disorder. The increase in antidepressant users was apparent across the whole brain and in the SMN when investigating subnetworks. These findings help disentangle how antidepressants improve symptoms.

Development of a body dysmorphic disorder screener for DSM-5 (BDDS-5).

Early identification of individuals with Body dysmorphic disorder (BDD) is essential to direct them to appropriate care and to reduce the chance of developing or maintaining comorbid psychiatric disorders (like an eating disorder (ED)). The present study aimed to develop a simple screener, the Body Dysmorphic Disorder Screener for DSM-5 (BDDS-5), to overcome existing screeners' limitations and test its psychometric properties. The BDDS-5 consists of 12 statements with dichotomous answer options. Specific attention is paid to the readability of the screener for those with lower reading skills. Additional eating disorder screening questions (S section) were added to investigate whether these questions are necessary for detecting potential BDD cases. Finally, the factor structure, internal consistency, and validity of the BDDS-5 were examined within populations with a high risk of screening positive for BDD or ED. Principal axis factor analysis showed that two factors accounted for 63.5% of the variance. The factor analysis was based on polychoric correlation. Based on the BDDS-5, 33 persons (14% of N = 235) were screened as likely BDD cases. Nineteen persons were excluded as potential BDD cases based on the eating disorder related question (question D). Based on the S-section, this turned out to be largely correct for the majority, however, in 8% (n = 4) of the cases BDD was probably missed. The convergent validity appeared to be high (r > 0.80) with three other BDD measures. The BDDS-5 is a valid and widely applicable screener for BDD that may help in the early detection of BDD. The BDDS-5 uses simple wording and is thus suitable for people 8 years and older.

Potential associations between immune signaling genes, deactivated microglia, and oligodendrocytes and cortical gray matter loss in patients with long-term remitted Cushing's disease.

INTRODUCTION: Cushing's disease (CD) is a rare and severe endocrine disease characterized by hypercortisolemia. Previous studies have found structural brain alterations in remitted CD patients compared to healthy controls, specifically in the anterior cingulate cortex (ACC). However, potential mechanisms through which these persistent alterations may have occurred are currently unknown. METHODS: Structural 3T MRI's from 25 remitted CD patients were linked with gene expression data from neurotypical donors, derived from the Allen Human Brain Atlas. Differences in gene expression between the ACC and an unaffected control cortical region were examined, followed by a Gene Ontology (GO) enrichment analysis. A cell type enrichment analysis was conducted on the differentially expressed genes, and a disease association enrichment analysis was conducted to determine possible associations between differentially expressed genes and specific diseases. Subsequently, cortisol sensitivity of these genes in existing datasets was examined. RESULTS: The gene expression analysis identified 300 differentially expressed genes in the ACC compared to the cortical control region. GO analyses found underexpressed genes to represent immune function. The cell type specificity analysis indicated that underexpressed genes were enriched for deactivated microglia and oligodendrocytes. Neither significant associations with diseases, nor evidence of cortisol sensitivity with the differentially expressed genes were found. DISCUSSION: Underexpressed genes in the ACC, the area vulnerable to permanent changes in remitted CD patients, were often associated with immune functioning. The specific lack of deactivated microglia and oligodendrocytes implicates protective effects of these cell types against the long-term effects of cortisol overexposure.

Fifteen years of NESDA Neuroimaging: An overview of results related to clinical profile and bio-social risk factors of major depressive disorder and common anxiety disorders.

The longitudinal Netherlands Study of Depression and Anxiety (NESDA) Neuroimaging study was set up in 2003 to investigate whether neuroanatomical and functional abnormalities during tasks of primary emotional processing, executive planning and memory formation, and intrinsic brain connectivity are i) shared by individuals with major depressive disorder (MDD) and common anxiety disorders; and ii) characterized by symptomatology-specific abnormalities. Furthermore, questions related to individual variations in vulnerability for onset, comorbidity, and longitudinal course could be investigated. Between 2005 and 2007, 233 individuals fulfilling a diagnosis of MDD, panic disorder, social anxiety disorder and/or generalized anxiety disorder and 68 healthy controls aging between 18 and 57 were invited from the NESDA main sample (n = 2981). An emotional faces processing task, an emotional word-encoding task, and an executive planning task were administered during 3T BOLD-fMRI acquisitions. In addition, resting state BOLD-fMRI was acquired and T1-weighted structural imaging was performed. All participants were invited to participate in the two-year and nine-year follow-up MRI measurement. Fifteen years of NESDA Neuroimaging demonstrated common morphological and neurocognitive abnormalities across individuals with depression and anxiety disorders. It however provided limited support for the idea of more extensive abnormalities in patients suffering from both depression and anxiety, despite their worse prognosis. Risk factors including childhood maltreatment and specific risk genes had an emotion processing modulating effect, apparently stronger than effects of diagnostic labels. Furthermore, brain imaging data, especially during emotion processing seemed valuable for predicting the long-term course of affective disorders, outperforming prediction based on clinical information alone.

Salivary markers of stress system activation and social withdrawal in humans.

Social withdrawal is an early and common feature of psychiatric disorders. Hypothalamic-pituitary-adrenal (HPA)-axis activation through increased salivary cortisol (sC) and sympathetic activation through increased salivary alpha-amylase (sAA) may play a role. We aimed to study whether the link between increased sC and sAA on the one hand and depression on the other hand is mediated by social withdrawal. In this cross-sectional, observational study, sC and sAA measures were measured in seven saliva samples in 843 participants (231 psychiatric patients and 612 healthy controls). Social withdrawal was assessed through the Brief Symptom Inventory (BSI)-, the Short Form 36-, and the Dutch Dimensional Assessment of Personality Pathology social withdrawal subscales, and analyzed using linear regression and mediation analyses. On average, participants were 44.0 years old (SD = 12.8; 64.1% female). Basal and diurnal sAA were unrelated to any social withdrawal scale and depression. Certain sC measures were positively associated with the BSI social withdrawal subscale (i.e., area under the curve with respect to the increase, beta = 0.082, p = 0.02; evening sC value: beta = 0.110, p = 0.003; and mean sC value: beta = 0.097; p = 0.01). We found limited support for statistical mediation by social withdrawal (measured using a composite social withdrawal score) on the relationship between evening sC and depression. Thus, although we found no support for a role of basal and diurnal sAA in social withdrawal, HPA-axis activation may partly aggravate social withdrawal in depressive disorders.

Cortical thickness abnormalities in long-term remitted Cushing's disease.

Long-term remitted Cushing's disease (LTRCD) patients commonly continue to present persistent psychological and cognitive deficits, and alterations in brain function and structure. Although previous studies have conducted gray matter volume analyses, assessing cortical thickness and surface area of LTRCD patients may offer further insight into the neuroanatomical substrates of Cushing's disease. Structural 3T magnetic resonance images were obtained from 25 LTRCD patients, and 25 age-, gender-, and education-matched healthy controls (HCs). T1-weighted images were segmented using FreeSurfer software to extract mean cortical thickness and surface area values of 68 cortical gray matter regions and two whole hemispheres. Paired sample t tests explored differences between the anterior cingulate cortex (ACC; region of interest), and the whole brain. Validated scales assessed psychiatric symptomatology, self-reported cognitive functioning, and disease severity. After correction for multiple comparisons, ROI analyses indicated that LTRCD-patients showed reduced cortical thickness of the left caudal ACC and the right rostral ACC compared to HCs. Whole-brain analyses indicated thinner cortices of the left caudal ACC, left cuneus, left posterior cingulate cortex, right rostral ACC, and bilateral precuneus compared to HCs. No cortical surface area differences were identified. Cortical thickness of the left caudal ACC and left cuneus were inversely associated with anxiety symptoms, depressive symptoms, and disease duration, although certain associations did not persist after correction for multiple testing. In six of 68 regions examined, LTRCD patients had reduced cortical thickness in comparison to HCs. Cortical thickness of the left caudal ACC was inversely associated with disease duration. This suggests that prolonged and excessive exposure to glucocorticoids may be related to cortical thinning of brain structures involved in emotional and cognitive processing.

Decreased functional connectivity of the insula within the salience network as an indicator for prospective insufficient response to antidepressants.

Insufficient response to treatment is the main cause of prolonged suffering from major depressive disorder (MDD). Early identification of insufficient response could result in faster and more targeted treatment strategies to reduce suffering. We therefore explored whether baseline alterations within and between resting state functional connectivity networks could serve as markers of insufficient response to antidepressant treatment in two years of follow-up. We selected MDD patients (N = 17) from the NEtherlands Study of Depression and Anxiety (NESDA), who received ≥ two antidepressants, indicative for insufficient response, during the two year follow-up, a group of MDD patients who received only one antidepressant (N = 32) and a healthy control group (N = 19) matched on clinical characteristics and demographics. An independent component analysis (ICA) of baseline resting-state scans was conducted after which functional connectivity within the components was compared between groups. We observed lower connectivity of the right insula within the salience network in the group with ≥ two antidepressants compared to the group with one antidepressant. No difference in connectivity was found between the patient groups and healthy control group. Given the suggested role of the right insula in switching between task-positive mode (activation during attention-demanding tasks) and task-negative mode (activation during the absence of any task), we explored whether right insula activation differed during switching between these two modes. We observed that in the ≥2 antidepressant group, the right insula was less active compared to the group with one antidepressant, when switching from task-positive to task-negative mode than the other way around. These findings imply that lower right insula connectivity within the salience network may serve as an indicator for prospective insufficient response to antidepressants. This result, supplemented by the diminished insula activation when switching between task and rest related networks, could indicate an underlying mechanism that, if not sufficiently targeted by current antidepressants, could lead to insufficient response. When replicated, these findings may contribute to the identification of biomarkers for early detection of insufficient response.

General psychopathology factor and unresolved-disorganized attachment uniquely correlated to white matter integrity using diffusion tensor imaging.

BACKGROUND: A dimensional approach of psychopathology focuses on features and risk factors that are shared across diagnoses. In support for this dimensional approach, studies point to a general psychopathology factor (GPF) associated with risk for multiple psychiatric disorders. It is, however, unknown how GPF relates to white matter integrity (WMI). In the current diffusion tensor imaging (DTI) study, we examined how GPF relates to abnormalities in a skeleton representation of white matter tracts, taking into account a trans-diagnostic risk factor: unresolved-disorganized attachment (Ud) resulting from loss or trauma. METHODS: Unique associations between GPF, Ud, and WMI were examined in a combined sample of adolescents (N = 63) with childhood sexual abuse-related posttraumatic stress disorder (N = 18), anxiety and depressive disorders (N = 26) and without psychiatric disorder (N = 19). WMI was measured using DTI. Ud was measured using the Adult Attachment Interview. We controlled for puberty stage, gender, age, and IQ. RESULTS: Controlling for GPF, Ud was associated with reduced fractional anisotropy (FA) in the splenium and inferior fronto-occipital fasciculus (IFOF). Controlling for Ud, GPF was associated with reduced FA in the genu and body of the corpus callosum. CONCLUSIONS: Decreasing WMI in the genu and body with increasing psychopathology across diagnoses suggests demyelinization in these areas and may underlie comorbidity and presence of symptoms that transcend psychopathological diagnoses. In contrast, trauma-related WMI reductions in the splenium and IFOF may account for heterogeneity within diagnostic categories as a function of childhood trauma. These findings support the importance of a dimensional approach in addition to traditional diagnostic classifications in clinical research and practice.

Elevated salivary alpha-amylase levels at awakening in patients with depression.

BACKGROUND: Specific Major Depressive Disorder (MDD) biomarkers could help improve our understanding of MDD pathophysiology and aid in the refinement of current MDD criteria. While salivary cortisol (SC) can differentiate between healthy controls and patients with psychiatric disorders, salivary alpha amylase (sAA), may be a putative candidate biomarker for MDD specifically. METHODS: In a naturalistic cohort of consecutive out-patients and healthy controls, sAA and SC were determined in 833 participants (97 MDD patients, 142 patients with other mood, anxiety, and/or somatoform (MAS-) disorders, and 594 healthy controls). Samples were collected at 7 different time points (at awakening, after 30, 45, and 60 min, at 10:00 p.m., at 11:00 p.m., and at awakening on day 2). RESULTS: The mean age of the sample was 43.8 years (SD = 12.9; 63.9% female). Concerning sAA, MDD patients had higher sAA levels upon awakening on two consecutive days (p = 0.04, p = 0.01 respectively), as well as a higher area under the curve with respect to the increase (AUCi; p = 0.04) in comparison to both controls and the other MAS-disorders group. Regarding SC, mean levels of evening SC were elevated in MDD patients (p = 0.049) in comparison to both controls and the other MAS-disorders group. SC values on day 2 after ingestion of dexamethasone were elevated in both MDD patients and the other MAS-disorders group (p = 0.04, p = 0.047 respectively). CONCLUSIONS: sAA at awakening and not cortisol differentiates MDD from other psychiatric disorders in outpatients. This suggests that sAA may be a valuable candidate biomarker specifically for MDD.

Social functioning in patients with depressive and anxiety disorders.

OBJECTIVE: Adaptive social functioning is severely impeded in depressive and anxiety disorders, even after remission. However, a comprehensive overview is still lacking. METHOD: Using data from the Netherlands Study of Depression and Anxiety (NESDA), behavioural (network size, social activities, social support) and affective (loneliness, affiliation, perceived social disability) indicators of social functioning were analyzed in patients with anxiety (N = 540), depressive (N = 393), comorbid anxiety and depressive disorders ('comorbid', N = 748), remitted participants (N = 621), and healthy control subjects (N = 650). RESULTS: Analyses revealed an increasing trend of social dysfunction among patient groups, in patients with comorbid anxiety and depressive disorders, showing the most severe impairments, followed by depressed and anxious patients (P's < 0.001 for all social functioning indicators). Affective indicators showed the largest effect sizes (Cohen's d range from 0.13 to 1.76). We also found impairments in social functioning among remitted patients. Furthermore, perceived social disability among patients was predictive of still having a depressive and/or anxiety diagnosis 2 years later (P < 0.01). CONCLUSIONS: Behavioural but especially affective indicators of social functioning are impaired in patients with anxiety or depressive disorders and most in patients with comorbid disorders. After remission of affective psychopathology, residual impairments tend to remain, while social dysfunction in patients seems predictive of future psychopathology.

Outcomes of neuropsychiatric events in systemic lupus erythematosus based on clinical phenotypes; prospective data from the Leiden NP SLE cohort.

Objective The objective of this study was to assess whether clinical and patient's reported outcomes are associated with a different pathophysiological origin of neuropsychiatric events presenting in systemic lupus erythematosus. Methods A total of 232 neuropsychiatric events presenting in 131 systemic lupus erythematosus patients were included. Neuropsychiatric systemic lupus erythematosus diagnosis was established per event by multidisciplinary evaluation. All neuropsychiatric events were divided according to a suspected underlying pathophysiological process into one of the following: non-neuropsychiatric systemic lupus erythematosus related, inflammatory and ischaemic neuropsychiatric systemic lupus erythematosus. The clinical outcome of all neuropsychiatric events was determined by a physician-completed four-point Likert scale. Health-related quality of life was measured with the subscales of the patient-generated Short Form 36 (SF-36) health survey questionnaire. The change between scores at paired visits of all domain scores, mental component summary (SF-36 MCS) and physical component summary (SF-36 PCS) scores were retrospectively calculated and used as patient-reported outcome. The association among these outcomes and the different origin of neuropsychiatric events was obtained using multiple logistic regression analysis. Results The clinical status of 26.8% non-neuropsychiatric systemic lupus erythematosus events, 15.8% ischaemic neuropsychiatric systemic lupus erythematosus and 51.6% inflammatory neuropsychiatric systemic lupus erythematosus improved after re-assessment. Almost all SF-36 domains had a positive change at re-assessment in all groups independently of the origin of neuropsychiatric events. Neuropsychiatric systemic lupus erythematosus ( B = 0.502; p < 0.001) and especially inflammatory neuropsychiatric systemic lupus erythematosus ( B = 0.827; p < 0.001) had better clinical outcome, with change in disease activity being the only important predictor. The change in SF-36 MCS was also independently associated with neuropsychiatric systemic lupus erythematosus ( B = 5.783; p < 0.05) and inflammatory neuropsychiatric systemic lupus erythematosus ( B = 11.133; p < 0.001). Disease duration and change in disease activity were the only predictors in both cases. The change in SF-36 PCS was only negatively associated with age. Conclusion Inflammatory neuropsychiatric systemic lupus erythematosus events have better clinical outcome and meaningful improvement in SF-36 MCS than ischaemic neuropsychiatric systemic lupus erythematosus or non-neuropsychiatric systemic lupus erythematosus.

Common and distinct patterns of grey-matter volume alteration in major depression and bipolar disorder: evidence from voxel-based meta-analysis.

Finding robust brain substrates of mood disorders is an important target for research. The degree to which major depression (MDD) and bipolar disorder (BD) are associated with common and/or distinct patterns of volumetric changes is nevertheless unclear. Furthermore, the extant literature is heterogeneous with respect to the nature of these changes. We report a meta-analysis of voxel-based morphometry (VBM) studies in MDD and BD. We identified studies published up to January 2015 that compared grey matter in MDD (50 data sets including 4101 individuals) and BD (36 data sets including 2407 individuals) using whole-brain VBM. We used statistical maps from the studies included where available and reported peak coordinates otherwise. Group comparisons and conjunction analyses identified regions in which the disorders showed common and distinct patterns of volumetric alteration. Both disorders were associated with lower grey-matter volume relative to healthy individuals in a number of areas. Conjunction analysis showed smaller volumes in both disorders in clusters in the dorsomedial and ventromedial prefrontal cortex, including the anterior cingulate cortex and bilateral insula. Group comparisons indicated that findings of smaller grey-matter volumes relative to controls in the right dorsolateral prefrontal cortex and left hippocampus, along with cerebellar, temporal and parietal regions were more substantial in major depression. These results suggest that MDD and BD are characterised by both common and distinct patterns of grey-matter volume changes. This combination of differences and similarities has the potential to inform the development of diagnostic biomarkers for these conditions.

A cluster analysis of early onset in common anxiety disorders.

Early onset is regarded as an important characteristic of anxiety disorders, associated with higher severity. However, previous findings diverge, as definitions of early onset vary and are often unsubstantiated. We objectively defined early onset in social phobia, panic disorder, agoraphobia, and generalised anxiety disorder, using cluster analysis with data gathered in the general population. Resulting cut-off ages for early onset were ≤22 (social phobia), ≤31 (panic disorder), ≤21 (agoraphobia), and ≤27 (generalised anxiety disorder). Comparison of psychiatric comorbidity and general wellbeing between subjects with early and late onset in the general population and an outpatient cohort, demonstrated that among outpatients anxiety comorbidity was more common in early onset agoraphobia, but also that anxiety- as well as mood comorbidity were more common in late onset social phobia. A major limitation was the retrospective assessment of onset. Our results encourage future studies into correlates of early onset of psychiatric disorders.

Gender differences in outpatients with anxiety disorders: the Leiden Routine Outcome Monitoring Study.

BACKGROUND: Data from the general population show higher prevalence of different anxiety disorders in women as compared with men. We analysed gender differences in a naturalistic sample of outpatients with anxiety disorders in a mental healthcare setting. METHOD: Routine outcome monitoring data were collected from 1333 patients (age: 18-65; 63.3% women) fulfilling Diagnostic and Statistical Manual of Mental Disorders IV criteria of current anxiety disorder according to the Mini-International Neuropsychiatric Interview between 2004 through 2006. Data included Comprehensive Psychopathological Rating Scale, Brief Symptom Inventory (BSI), Short Form Health Survey (SF-36), Mood and Anxiety Symptom Questionnaire (MASQ). Chi-squared test and t-test were used to compare women with men for variables with parametric distributions, and Mann-Whitney test for non-parametric distribution. Adjustments for potential confounders (age, level of education, ethnicity and comorbidites) were made by logistic regression models (for discrete variables) or analysis of covariance. RESULTS: The female-to-male ratio (i.e., 844 women, 489 men) for any anxiety disorder was 1.73 : 1 (95% confidence interval [CI]: 1.63-1.83), with the strongest skewness for post-traumatic stress disorder (2.80 : 1) and the smallest one for social phobia (1.18 : 1). Compared with men, women reported more severe self-rating scores on the BSI (on average, the scores were 12.3% higher on 3 of 9 subscales: somatisation, interpersonal sensitivity and anxiety), SF-36 (self-reported generic health status was lower on 5 of 8 subscales: physical functioning, social functioning, physical problems, vitality and bodily pain) and MASQ (on average, the scores were 6.6% higher on 4 of 5 subscales: anxious arousal, general distress, general distress depression, general distress anxiety). On the contrary, no gender difference was found in the severity of anxiety symptoms measured by the Brief Anxiety Scale. Women were more likely to suffer from comorbid depression and bulimia nervosa, and less likely from substance abuse. CONCLUSIONS: In a treatment-seeking population the prevalence rate of anxiety disorders was 1.7 times higher in female compared with men. Female outpatients were more severely affected on self-rated but not on observer-rated scales.

Subcortical brain alterations in major depressive disorder: findings from the ENIGMA Major Depressive Disorder working group.

The pattern of structural brain alterations associated with major depressive disorder (MDD) remains unresolved. This is in part due to small sample sizes of neuroimaging studies resulting in limited statistical power, disease heterogeneity and the complex interactions between clinical characteristics and brain morphology. To address this, we meta-analyzed three-dimensional brain magnetic resonance imaging data from 1728 MDD patients and 7199 controls from 15 research samples worldwide, to identify subcortical brain volumes that robustly discriminate MDD patients from healthy controls. Relative to controls, patients had significantly lower hippocampal volumes (Cohen's d=-0.14, % difference=-1.24). This effect was driven by patients with recurrent MDD (Cohen's d=-0.17, % difference=-1.44), and we detected no differences between first episode patients and controls. Age of onset ⩽21 was associated with a smaller hippocampus (Cohen's d=-0.20, % difference=-1.85) and a trend toward smaller amygdala (Cohen's d=-0.11, % difference=-1.23) and larger lateral ventricles (Cohen's d=0.12, % difference=5.11). Symptom severity at study inclusion was not associated with any regional brain volumes. Sample characteristics such as mean age, proportion of antidepressant users and proportion of remitted patients, and methodological characteristics did not significantly moderate alterations in brain volumes in MDD. Samples with a higher proportion of antipsychotic medication users showed larger caudate volumes in MDD patients compared with controls. This currently largest worldwide effort to identify subcortical brain alterations showed robust smaller hippocampal volumes in MDD patients, moderated by age of onset and first episode versus recurrent episode status.