Early-onset Major Depressive Disorder Research Articles

Polygenic liabilities and treatment trajectories in early-onset depression: a Danish register-based study.

The clinical course of major depressive disorder (MDD) is heterogeneous, and early-onset MDD often has a more severe and complex clinical course. Our goal was to determine whether polygenic scores (PGSs) for psychiatric disorders are associated with treatment trajectories in early-onset MDD treated in secondary care. Data were drawn from the iPSYCH2015 sample, which includes all individuals born in Denmark between 1981 and 2008 who were treated in secondary care for depression between 1995 and 2015. We selected unrelated individuals of European ancestry with an MDD diagnosis between ages 10-25 (N = 10577). Seven-year trajectories of hospital contacts for depression were modeled using Latent Class Growth Analysis. Associations between PGS for MDD, bipolar disorder, schizophrenia, ADHD, and anorexia and trajectories of MDD contacts were modeled using multinomial logistic regressions. We identified four trajectory patterns: brief contact (65%), prolonged initial contact (20%), later re-entry (8%), and persistent contact (7%). Relative to the brief contact trajectory, higher PGS for ADHD was associated with a decreased odds of membership in the prolonged initial contact (odds ratio = 1.06, 95% confidence interval = 1.01-1.11) and persistent contact (1.12, 1.03-1.21) trajectories, while PGS-AN was associated with increased odds of membership in the persistent contact trajectory (1.12, 1.03-1.21). We found significant associations between polygenic liabilities for psychiatric disorders and treatment trajectories in patients with secondary-treated early-onset MDD. These findings help elucidate the relationship between a patient's genetics and their clinical course; however, the effect sizes are small and therefore unlikely to have predictive value in clinical settings.

Childhood maltreatment and suicide attempts in major depression and bipolar disorders in South Korea: A prospective nationwide cohort study

BackgroundChildhood maltreatment (CM) is prevalent among patients with mood disorders and considered an important risk factor for suicide in the general population. Despite mood disorders being implicated in up to 60 % of completed suicides, the predictive role of CM on suicide attempt (SA) among early mood disorder patients remains poorly understood. MethodsWe enrolled 480 participants diagnosed with early-onset major depressive disorder (MDD), bipolar I disorder (BD I), and bipolar II disorder (BD II). Over an average of 60 weeks, participants underwent follow-up assessments at 12-week intervals. Using multivariate logistic regression, we examined the association between CM and SA history at baseline. Further, the Cox proportional hazard model assessed the predictive role of childhood maltreatment in SA during follow-up. ResultsAt baseline, 38 % of the total participants reported SA history, with a follow-up prevalence of 10 %. Childhood maltreatment was significantly associated with past SAs and was a robust predictor of future SA, adjusting for relevant clinical risk factors. Emotional abuse and sexual abuse related to SA history, and physical abuse increased future SA risk. LimitationsPotential biases in reporting SA and childhood maltreatment, along with unexplored factors such as additional environmental and familial risks, may affect the study's findings. ConclusionsChildhood maltreatment emerged as a robust predictor of SA among early-onset mood disorder patients. Systematic evaluation of CM early in the clinical process may be crucial for effective risk management. Additionally, our findings highlight the importance of implementing proactive interventions for CM to prevent the onset of adverse psychological trajectories.

Tissue-specific gene expression of genome-wide significant loci associated with major depressive disorder subtypes

Major depressive disorder (MDD) is a clinically and genetically heterogeneous disorder. To reduce heterogeneity, large-scale genome-wide association studies have recently identified genome-wide significant loci associated with seven MDD subtypes. However, it was unclear in which tissues the genes near those loci are specifically expressed. We investigated whether genes related to specific MDD subtypes would be preferably expressed in a specific tissue. At 14 novel subtype-specific loci related to seven MDD subtypes—(1) non-atypical-like features MDD, (2) early-onset MDD, (3) recurrent MDD, (4) MDD with suicidal thoughts, (5) MDD without suicidal thoughts, (6) MDD with moderate impairment, and (7) postpartum depression, we investigated whether 22 genome-wide significant genetic variant-mapped genes were tissue-specifically expressed in brain, female reproductive, male specific, cardiovascular, gastrointestinal, or urinary tissues in the Genotype-Tissue Expression (GTEx) subjects (n ≤ 948). To confirm the tissue-specific expression in the GTEx, we used independent Human Protein Atlas (HPA) RNA-seq subjects (n ≤ 95). Of 22 genes, nine and five genes were tissue-specifically expressed in brain and female reproductive tissues, respectively (p < 2.27 × 10−3). RTN1, ERBB4, and AMIGO1 related to early-onset MDD, recurrent MDD, or MDD with suicidal thoughts were highly expressed in brain tissues (d = 1.19–2.71), while OAS1, LRRC9, DHRS7, PSMA5, SYPL2, and GULP1 related to non-atypical-like features MDD, early-onset MDD, MDD with suicidal thoughts, or postpartum depression were expressed at low levels in brain tissues (d = −0.17−−1.48). DFNA5, CTBP2, PCNX4, SDCCAG8, and GULP1, which are related to early-onset MDD, MDD with moderate impairment, or postpartum depression, were highly expressed in female reproductive tissues (d = 0.80–2.08). Brain and female reproductive tissue-specific expression was confirmed in the HPA RNA-seq subjects. Our findings suggest that brain and female reproductive tissue-specific expression might contribute to the pathogenesis of MDD subtypes.

Differences in the prevalence and clinical correlates of comorbid suicide attempts in patients with early- and late-onset major depressive disorder.

There are many studies on differences in the onset age of major depressive disorder (MDD) patients. However, study on differences in clinical correlates of suicide attempts between early- and late-onset MDD patients is limited. The aim of this study was to investigate the differences in the prevalence and clinical correlates of suicide attempts in patients with early- and late-onset MDD in China. A total of 1718 adult outpatients with MDD were recruited. Demographic and clinical data were collected. The 17-item Hamilton Rating Scale for Depression (HAMD-17), Hamilton Anxiety Rating Scale (HAMA), Positive and Negative Syndrome Scale (PANSS) positive subscale, and Clinical Global Impression-Severity (CGI-S) Scales were used to assess their depressive, anxiety, psychotic symptoms, and the severity of the clinical symptoms, respectively. The prevalence of suicide attempts was higher in late-onset MDD patients (291/1369, 21.3%) than in early-onset MDD patients (55/349, 15.8%) (p = 0.023). However after Bonferroni correction no significant difference was found in the prevalence of suicide attempts in late-onset and late-onset MDD patients (p > 0.05). In both early- and late-onset groups, univariate analysis showed that the following characteristics were significantly associated with suicide attempts: HAMA, HAMD and PANSS positive subscale scores, thyroid stimulating hormone (TSH) levels, blood glucose levels, systolic blood pressure (SBP), and diastolic blood pressure (DBP). In both the early- and late-onset groups, the prevalence rates of severe anxiety disorder and psychotic symptoms were significantly higher in the suicide attempt group than in the non-suicide attempt group. In regression analysis, disease duration, TSH levels and HAMA score were independently associated with suicide attempts in the early-onset group, while TSH levels, HAMA and HAMD score were independently associated with suicide attempts in the late-onset group. This study suggests that suicide attempts are not frequent in early-onset outpatients with MDD compared with late-onset, and some clinical correlates are associated with suicide attempt in early- and late-onset MDD.

Normative modeling analysis reveals corpus callosum volume changes in early and mid-to-late first episode major depression

BackgroundIt has been widely accepted that major depressive disorder (MDD) impacts brain structures including the Corpus Callosum (CC). However, this assumption is based on scarce literature data involving small sample sizes. Furthermore, it is still unclear whether such CC volume changes may already be present at a first depressive episode. MethodsTo further investigate this question, we compared 369 first-episode MDD patients (mean age = 35 years (sd = 12), 249 females; 283 early onset, 86 mid-to-late onset) from the open-source REST meta-MDD database closely matched for age and gender to 490 never-depressed individuals (mean age = 37 years (sd = 14); 309 females) using Z-scores obtained from normative neuroanatomical modeling to assess individual variability in CC (sub)volumes. ResultsRelative to the norms established by the healthy controls, first-episode MDD patients displayed CC volume (z-score) reductions in the entire CC (including the body), as did mid-to-late-onset first-episode MDD patients (age ≥ 45 y). In early-onset first-episode MDD patients (age ≤ 44 y), depression severity symptoms were related to volume increases in the entire CC, as well as the body and splenium. LimitationsNo data on depressive episode duration. Relatively small sample size for mid-to-late first-episode MDD patients. ConclusionsOur data revealed CC (sub)volume differences in early versus mid-to-late onset first episode MDD. Especially at early onset, depression severity may result in neural white matter activity as potential reaction to stress influences. Our results underline the importance of prompt clinical interventions at early onset MDD.

Eveningness and Impulsivity in Euthymic Mood States Adversely Affect the Quality of Life of Major Depression and Bipolar Disorder Patients

Objective: Chronotype and impulsivity are important features to be examined in mood disorder patients; these characteristics precede mood disorder onset and persist between mood episodes. Moreover, quality of life is an important outcome in psychiatric patients. This study investigated the interaction between these features and its effect on mood disorder patient’s quality of life.Methods: Early-onset major depressive disorder (MDD), bipolar disorder I (BD I), and bipolar disorder II (BD II) patients were recruited. Excluding 18 patients who were missing data on main variables and 5 patients who were classified as severely ill, a total of 472 euthymic patients (MDD=167, BD I=133, BD II= 172) were assessed on their chronotype, trait impulsivity, and quality of life using self-reports.Results: Both impulsivity and eveningness were negatively associated with quality of life. Regression results showed that there was a significant interaction effect between eveningness and impulsivity on quality of life. This indicates that the higher the level of impulsivity in mood disorder patients, the negative effect of eveningness on quality of life increased.Conclusion: The current study suggests that examination of impulsive personality in relation to chronotype may be important in further understanding the effects of these features on mood disorder patients’ lives.

Earlier age of onset is associated with a pro-inflammatory state in major depressive disorder

Major depressive disorder (MDD) is a common condition that affects the general population over a wide range of ages, regardless of gender and social background. Early-onset of MDD in adulthood, between ages of 18 and 30 years, is associated with worse outcomes and increased years of disability. Stress load and physical health have been associated with age of onset in MDD. We aim to investigate whether early onset MDD might be associated with changes in systemic inflammatory markers. We examined levels of following cytokines: IL-1β, IL-6, IL-10 and TNFα in 234 patients with MDD. Higher serum levels of TNFα and IL-1β are associated with the early onset of the disorder in patients with MDD. IL-6 levels were also higher in the early onset group and IL-10 levels were higher in the late onset group, but with no significant difference. Changes in the anti-inflammatory/pro-inflammatory balance have been described in mood disorders and may be implicated in its severity and pattern of progression. Our findings reinforce that higher serum levels of IL-1β and TNFα may be associated with the earlier onset subgroup of MDD patients. Future research that target inflammatory markers of immune modulation may be, key in the search for novel preventative therapeutics.

Environmental factors in offspring of parents with mood disorders and their role in parent\u2013child transmission: findings from a 14-year prospective high-risk study

BackgroundThe factors involved in the transmission of mood disorders are only partially elucidated. Aside from genes, the family environment might play a crucial role in parent–child transmission. Our goals were to (1) assess the associations of parental bipolar disorder (BPD) and Major Depressive Disorder (MDD) with individual or shared family environmental factors, including traumatic events in offspring, parental separation, family cohesion and parental attitudes; and 2) test whether these factors were mediators of the association between exposure to parental mood disorders and the onset of these disorders in offspring.MethodsThe sample stems from an ongoing family high-risk study of mood disorders conducted in the French-speaking part of Switzerland. Given the strong impact of the age of onset of parental disorders on their transmission to children, parental disorders were dichotomized according to the onset (cut-off 21 years). Probands with early-onset (n = 30) and later-onset BPD (n = 51), early-onset (n = 21) and later-onset MDD (n = 47) and controls (n = 65), along with their spouses (n = 193) and offspring (n = 388; < 18 years on study inclusion), were assessed over a mean follow-up duration of 14 years (s.d: 4.6). The environmental measures were based on reports by offspring collected before the onset of their first mood episode.ResultsOffspring of probands with later-onset BPD and offspring of probands with both early-onset and later-onset MDD reported traumatic events more frequently than comparison offspring, whereas exposure to parental separation was more frequent in all groups of high-risk offspring. Moreover, several familial environment scores including parenting attitudes differed between offspring of probands with BPD and comparison offspring. However, none of these factors were mediators of the parent–child transmission of BPD. Among the environmental factors, traumatic events were shown to be modest mediators of the transmission of early-onset MDD.ConclusionsOur data do not support the implication of the assessed environmental factors in the parent–child transmission of BPD. In contrast to BPD, traumatic events partially mediate the parent–child transmission of early-onset MDD, which has important implications for intervention and prevention. Early therapeutic efforts in offspring exposed to these events are likely to reduce their deleterious impact on the risk of subsequent MDD.

Age-related heterogeneity revealed by disruption of white matter structural networks in patients with first-episode untreated major depressive disorder: WM Network In OA-MDD

The clinical treatment and prognosis of major depressive disorder (MDD) are limited by the high degree of disease heterogeneity. It is unclear whether there is a potential network mechanism for age-related heterogeneity. We aimed to uncover the heterogeneity of the white matter (WM) network at different ages of onset and its correlation with different symptom characteristics. 85 first-episode MDD patients and 84 corresponding healthy controls (HCs) were recruited and underwent diffusion tensor imaging scans. Structural network characteristics were analyzed using graph theory methods. We observed an accelerated age-related decline of the WM network in MDD patients compared with HCs. Distinct symptom-related networks were identified in three MDD groups with different onset-age. For early-onset MDD (18–29 years; EOD), higher guilt and loss of interest were correlated with the insula, and inferior parietal lobe which in default mode network and salience network. For mid-term-onset MDD (30–44 years; MOD), higher somatic symptoms were correlated with thalamus which in cortico-striatal-thalamic-cortical circuit. For later-onset MDD (45–60 years; LOD), poor sleep symptoms were correlated with the caudate in the basal ganglia, which suggests the cingulate operculum network in the control of sleep. These results supported a circuit-based heterogeneity associated with the age of onset in MDD. Understanding this circuit-based heterogeneity might help to develop a new target for clinical treatment strategies.

Childhood trauma and the plasma levels of IL-6, TNF-α are risk factors for major depressive disorder and schizophrenia in adolescents: A cross-sectional and case-control study

BackgroundIt has been reported that childhood trauma and inflammation are associated with major depressive disorder (MDD) and schizophrenia (SZ), but previous researches were almost aimed at adults. The aim of the present research is to observe the alteration of peripheral interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) in adolescents (12–20 years) with MDD and SZ, to investigate the impact of childhood abuse in early-onset MDD and SZ, and to furtherly explore the correlation between childhood maltreatment and plasma IL-6, TNF-α levels. Subjects and MethodsEnzyme-linked immunosorbent assay (ELISA) is applied to obtain the plasma concentrations of IL-6 and TNF-α in 55 patients with MDD, 51 patients with SZ and 47 healthy minors. The short form of the Childhood Trauma Questionnaire (CTQ-SF) is used to assess the severity of early trauma. ResultsPlasma IL-6 and TNF-α levels are significantly elevated in patients with early-onset MDD and SZ compared with healthy subjects (p <0.01), whose results display that the correlation between IL-6 and TNF-α is significantly positive (γ=0.787, p <0.01) in all participants. Compared with the healthy adolescents, patients with MDD and SZ show more serious childhood trauma, and the plasma IL-6, TNF-α concentrations are closely related to childhood maltreatment. ConclusionsEarly trauma and peripheral inflammatory response play an important role in the pathophysiology of early-onset MDD or SZ. The current findings provide effective targets for the prevention, diagnosis, and treatment of major depressive disorder and schizophrenia in adolescents.

Fibroblast growth factor 21 (FGF21) is increased in MDD and interacts with body mass index (BMI) to affect depression trajectory

Fibroblast growth factor 21 (FGF21) is a key regulator of metabolic function and nutrient preference. It also affects biological pathways associated with major depressive disorder (MDD), including corticotrophin-releasing hormone (CRH), leptin, and sympathetic activity. Lower levels of cerebrospinal fluid FGF21 have been associated with higher Beck Depression Inventory scores. FGF21 was examined as a metabolic marker that could be associated with MDD and evaluated as a biomarker of antidepressant treatment response in a large, randomized placebo-controlled trial in chronic, early-onset MDD participants. FGF21 levels at baseline and during treatment were determined for participants in the Establishing Moderators and Biosignatures of Antidepressant Response for Clinical Care (EMBARC) study. FGF21 was analyzed by ELISA in individuals with chronic, early-onset MDD (first major depressive episode before 30 years) compared to healthy control participants. Participants with MDD had higher levels of FGF21 compared to healthy controls (HCs), even after controlling for baseline age, sex, race, Hispanic ethnicity, BMI, and site (β-coefficient = 1.20, p < 0.0001, Cohen’s d = 0.60). FGF21 did not change over time nor differ between treatment groups. Interestingly though, those with normal BMI and lower FGF21 levels showed a reduction in depression severity over time compared to all other groups. In conclusion, depression is associated with higher levels of FGF21 compared to healthy controls and those with lower levels of FGF21 (25th percentile of the sample) in the context of normal-weight BMI seem to have improved depression severity over time.

Hippocampal and Hippocampal-Subfield Volumes From Early-Onset Major Depression and Bipolar Disorder to Cognitive Decline.

Background: The hippocampus and its subfields (HippSub) are reported to be diminished in patients with Alzheimer's disease (AD), bipolar disorder (BD), and major depressive disorder (MDD). We examined these groups vs healthy controls (HC) to reveal HippSub alterations between diseases.Methods: We segmented 3T-MRI T2-weighted hippocampal images of 67 HC, 58 BD, and MDD patients from the AFFDIS study and 137 patients from the DELCODE study assessing cognitive decline, including subjective cognitive decline (SCD), amnestic mild cognitive impairment (aMCI), and AD, via Free Surfer 6.0 to compare volumes across groups.Results: Groups differed significantly in several HippSub volumes, particularly between patients with AD and mood disorders. In comparison to HC, significant lower volumes appear in aMCI and AD groups in specific subfields. Smaller volumes in the left presubiculum are detected in aMCI and AD patients, differing from the BD group. A significant linear regression is seen between left hippocampus volume and duration since the first depressive episode.Conclusions: HippSub volume alterations were observed in AD, but not in early-onset MDD and BD, reinforcing the notion of different neural mechanisms in hippocampal degeneration. Moreover, duration since the first depressive episode was a relevant factor explaining the lower left hippocampal volumes present in groups.

Lifetime major depression and grey-matter volume

There is evidence of structural brain alterations in major depressive disorder (MDD), but little is known about how these alterations might be affected by age at onset or genetic vulnerability. This study examines whether lifetime episodes of MDD are associated with specific alterations in grey-matter volume, and whether those alterations vary according to sex or serotonin transporter-linked promoter region (5-HTTLPR) genotype (LL, SL or SS). We used structural MRI to acquire anatomic scans from 610 community-dwelling participants. We derived quantitative regional estimates of grey-matter volume in 16 subregions using FreeSurfer software. We diagnosed MDD according to DSM-IV criteria. We adjusted analyses for age, sex, total brain volume, education level, head injury and comorbidities. Lifetime MDD was associated with a smaller insula, thalamus, ventral diencephalon, pallidum and nucleus accumbens and with a larger pericalcarine region in both men and women. These associations remained after adjustment for false discovery rate. Lifetime MDD was also associated with a smaller caudate nucleus and amygdala in men and with a larger rostral anterior cingulate cortex in women. Late-onset first episodes of MDD (after age 50 years) were associated with a larger rostral anterior cingulate cortex and lingual and pericalcarine regions; early-onset MDD was associated with a smaller ventral diencephalon and nucleus accumbens. Some associations differed according to 5-HTTLPR genotype: the thalamus was smaller in participants with MDD and the LL genotype; pericalcarine and lingual volumes were higher in those with the SL genotype. This study was limited by its cross-sectional design. Major depressive disorder was associated with persistent volume reductions in the deep nuclei and insula and with enlargements in visual cortex subregions; alterations varied according to age of onset and genotype.

43 - GENOME-WIDE ASSOCIATION ANALYSES IDENTIFY 44 RISK VARIANTS AND REFINE THE GENETIC ARCHITECTURE OF MAJOR DEPRESSIVE DISORDER

Background Major Depressive Disorder (MDD) is a notably complex illness with a lifetime prevalence of 14%. It is often chronic or recurrent and is thus accompanied by considerable morbidity, excess mortality, substantial costs, and heightened risk of suicide. MDD is a major cause of disability worldwide. Twin studies attribute ~40% of the variation in liability to MDD to additive genetic effects, and may be greater for recurrent, early-onset, and postpartum MDD. GWA studies of MDD have had notable difficulties in identifying loci. Previous findings suggest that an appropriately designed study should identify susceptibility loci. Methods We conducted a Genome-Wide Association (GWA) meta-analysis in 130,664 MDD cases and 330,470 controls. We used the standard GWA mega/meta-analysis methods of the core PGC quality control, imputation, and analysis pipeline (i.e., ricopili) Results We identified 44 independent loci that met criteria for statistical significance. We can make a strong case for the identification of RBFOX1 and NEGR1. The genetic findings were associated with clinical features of MDD, and implicated prefrontal and anterior cingulate cortex in the pathophysiology of MDD (regions exhibiting anatomical differences in MDD cases vs controls). Genes that are targets of antidepressant medications were strongly enriched for MDD association signals (P=8.5e-10), suggesting the relevance of these findings for improved pharmacotherapy of MDD. Sets of genes involved in gene splicing and in creating isoforms were also enriched for smaller MDD GWA P-values, and these gene sets have also been implicated in schizophrenia and autism. Genetic risk for MDD was correlated with that for many adult and childhood onset psychiatric disorders. Our analyses suggested important relations of genetic risk for MDD with educational attainment, body mass, and schizophrenia: the genetic basis of lower educational attainment and higher body mass were putatively causal for MDD whereas MDD and schizophrenia reflected a partly shared biological etiology. Discussion We present extensive analyses of these results which provide new insights into the nature of MDD. All humans carry lesser or greater numbers of genetic risk factors for MDD, and a continuous measure of risk underlies the observed clinical phenotype. MDD is not a distinct entity that neatly demarcates normalcy from pathology but rather a useful clinical construct associated with a range of adverse outcomes and the end result of a complex process of intertwined genetic and environmental effects. These findings help refine and define the fundamental basis of MDD.

Intrinsic thalamocortical connectivity varies in the age of onset subtypes in major depressive disorder.

BackgroundDifferences in the thalamocortical system have been shown in patients with major depressive disorder (MDD). Given prior evidence of phenotypic heterogeneity by the age of onset in MDD, we examined whether differences in thalamocortical connectivity could identify biological subtypes of MDD defined by the age of illness onset.MethodsA total of 94 subjects including 20 early-onset (EO) MDD (onset, 18 years), 34 adult-onset (AO) MDD, and 40 healthy controls (HCs) underwent resting-state functional MRI. Blood-oxygen-level-dependent time courses were extracted from six cortical regions of interest (ROIs) consisting of frontal, temporal, parietal, and occipital lobes and precentral and postcentral gyri. Each ROI’s time course was then correlated with each voxel in thalamus, while covarying out signal from every other ROI.ResultsThe analysis of variance results showed significant main effects of group in frontal and temporal connectivity with thalamus. Group contrasts showed a right fronto-thalamic hypo-connectivity only in AO-MDD, but not in EO-MDD, when compared to HCs. However, direct comparison between EO-MDD and AO-MDD showed no differences. Furthermore, there was a right temporal–thalamic hyperconnectivity in both EO-MDD and AO-MDD patients relative to HCs. These results were not accounted for by sex, age, or illness burden.ConclusionThe age of illness onset may be a source of heterogeneity in fronto-thalamic intrinsic connectivity in MDD.

Anxiety and anhedonia in depression: Associations with neuroticism and cognitive control

BackgroundDespite the fact that higher levels of anxiety and anhedonia in Major Depressive Disorder (MDD) are linked to poorer treatment outcomes, mechanisms contributing to these clinical presentations remain unclear. Neuroticism, impaired cognitive control, and blunted reward learning may be critical processes involved in MDD and may help to explain symptoms of anxiety and anhedonia. MethodsUsing baseline data from patients with early-onset MDD (N = 296) in the Establishing Moderators and Biosignatures of Antidepressant Response in Clinical Care (EMBARC) trial, we conducted a path analysis to model relationships between neuroticism, cognitive control, and reward learning to levels of anxiety and anhedonia. ResultsNeuroticism was positively associated with both anhedonia (standardized coefficient = 0.26, p < .001) and anxiety (standardized coefficient = 0.40, p < .001). Cognitive control was negatively associated with anxiety (standardized coefficient = -0.18, p < .05). Reward learning was not significantly associated with either anxiety or anhedonia. LimitationsExtraneous variables not included in the model may have even more influence in explaining symptoms of anxiety and anhedonia. Restricted range in these variables may have attenuated some of the hypothesized relationships. Most important, because this was a cross-sectional analysis in a currently depressed sample, we cannot draw any causal conclusions without experimental and longitudinal data. ConclusionsThese cross-sectional findings suggest that neuroticism may contribute to anxiety and anhedonia in patients with early onset and either chronic or recurrent MDD, while enhanced cognitive control may protect against anxiety.

Cognitive control neuroimaging measures differentiate between those with and without future recurrence of depression

BackgroundMajor Depressive Disorder (MDD) is a prevalent, disruptive illness. A majority of those with MDD are at high risk for recurrence and increased risk for morbidity and mortality. This study examined whether multimodal baseline (and retest) Cognitive Control performance and neuroimaging markers (task activation and neural connectivity between key brain nodes) could differentiate between those with and without future recurrence of a major depressive (MD) episode within one year. We hypothesized that performance and neuroimaging measures of Cognitive Control would identify markers that differ between these two groups.MethodsA prospective cohort study of young adults (ages 18–23) with history (h) of early-onset MDD (N = 60), now remitted, and healthy young adults (N = 49). Baseline Cognitive Control measures of performance, task fMRI and resting state connectivity (and reliability retest 4–12 weeks later) were used to compare those with future recurrence of MDD (N = 21) relative to those without future recurrence of MDD (N = 34 with resilience). The measures tested were (1) Parametric Go/No-Go (PGNG) performance, and task activation for (2) PGNG Correct Rejections, (3) PGNG Commission errors, and (4 & 5), resting state connectivity analyses of Cognitive Control Network to and from subgenual anterior cingulate.ResultsRelative to other groups at baseline, the group with MDD Recurrence had less bilateral middle frontal gyrus activation during commission errors. MDD Recurrence exhibited greater connectivity of right middle frontal gyrus to subgenual anterior cingulate (SGAC). SGAC connectivity was also elevated in this group to numerous regions in the Cognitive Control Network. Moderate to strong ICCs were present from test to retest, and highest for rs-fMRI markers. There were modest, significant correlations between task, connectivity and behavioral markers that distinguished between groups.ConclusionMarkers of Cognitive Control function could identify those with early course MD who are at risk for depression recurrence. Those at high risk for recurrence would benefit from maintenance or preventative treatments. Future studies could test and validate these markers as potential predictors, accounting for sample selection and bias in feature detection.

Antecedents of New-Onset Major Depressive Disorder in Children and Adolescents at High Familial Risk

Early-onset major depressive disorder (MDD) is common in individuals at high familial risk of depression and is associated with poor long-term mental health, social, and educational outcomes. To examine the developmental pathways that lead to first-episode adolescent-onset MDD (incident cases) in those at high familial risk and to postulate a theoretically informed model that enables simultaneous testing of different pathways to incident adolescent-onset MDD composed of contributions from familial/genetic and social risk factors, as well as effects via specific clinical antecedents. This investigation was a 4-year longitudinal study (April 2007 to March 2011) among offspring of depressed parents in the general community. Analyses were conducted between September 1, 2015, and May 27, 2016. Participants were 337 families in whom the index parent (315 mothers and 22 fathers) had experienced at least 2 episodes of MDD (recruited through primary care) and among whom there was a biologically related child in the age range of 9 to 17 years living with the index parent (197 girls and 140 boys with a mean [SD] age of 12.4 [2.0] years) at baseline. Offspring with MDD before the study or at baseline (n = 27), offspring with an episode of MDD that had remitted by follow-up (n = 4), and offspring with missing baseline MDD data (n = 2) were excluded. Ninety-two percent (279 of 304) of families completed the follow-up. The primary outcome was new-onset offspring MDD, and the secondary outcome was the total DSM-IV MDD symptom score. On average, children and adolescents had a mean (SD) of 1.85 (1.74) (range, 0-8.5) DSM-IV symptoms of MDD at follow-up. Twenty (6 males and 14 females) had new-onset MDD, with a mean (SD) age at onset of 14.4 (2.0) years (range, 10-18 years). Irritability (β = 0.12, P = .03) and fear and/or anxiety (β = 0.38, P < .001) were significant independent clinical antecedents of new adolescent-onset MDD, but disruptive behavior (β = -0.08, P = .14) and low mood (β = -0.03, P = .65) were not. The results were similar for the DSM-IV symptom count at follow-up. All the measured familial/genetic and social risk indicators directly influenced risk for new-onset MDD rather than indirectly through acting on dimensional clinical antecedents. There are multiple pathways to first-onset adolescent depression in individuals at familial risk. Irritability and fear/anxiety may be additional clinical phenomena to be included as targets in primary preventive interventions focusing on the child. In addition to targeting these phenomena in parents and children, depression prevention methods in high-risk groups may need to take into consideration social risks, such as poverty and psychosocial adversity.

Identifying key parent-reported symptoms for detecting depression in high risk adolescents

Adolescent offspring of depressed parents are at particularly heightened risk of developing early onset Major Depressive Disorder (MDD) yet are unlikely to access services. We therefore aimed to identify a parsimonious combination of parent-reported symptoms that accurately detected offspring MDD. We used a multi-sample study comprising a development sample of 335 offspring of adults with recurrent MDD assessed on three occasions (mean age 12.4–14.8 years) and an independent validation sub-sample of 807 adolescents from a general population cohort (mean age 13.1 years). Parent ratings of psychiatric symptoms in adolescent offspring were assessed using established questionnaires. The best performing four-item combination of symptoms was identified. Accuracy in detecting concurrent DSM-IV MDD diagnosis, assessed by direct adolescent and parent interviews, was compared to the well-established 13-item short Moods and Feelings Questionnaire (sMFQ) using ROC curve analysis. The combination identified (concentration problems, anhedonia, worrying excessively and feeling unloved) performed equivalently to the sMFQ both in the development dataset and in the validation dataset. We concluded that a combination of four parent-reported mental health items performs equivalently to an established, longer depression questionnaire measure in detecting a diagnosis of adolescent major depressive disorder among offspring of parents with recurrent MDD and needs further evaluation.

Novel variants in ZNF34 and other brain-expressed transcription factors are shared among early-onset MDD relatives.

There are no known genetic variants with large effects on susceptibility to major depressive disorder (MDD). Although one proposed study approach is to increase sensitivity by increasing sample sizes, another is to focus on families with multiple affected individuals to identify genes with rare or novel variants with strong effects. Choosing the family-based approach, we performed whole-exome analysis on affected individuals (n = 12) across five MDD families, each with at least five affected individuals, early onset, and prepubertal diagnoses. We identified 67 genes where novel deleterious variants were shared among affected relatives. Gene ontology analysis shows that of these 67 genes, 18 encode transcriptional regulators, eight of which are expressed in the human brain, including four KRAB-A box-containing Zn(2+) finger repressors. One of these, ZNF34, has been reported as being associated with bipolar disorder and as differentially expressed in bipolar disorder patients compared to healthy controls. We found a novel variant-encoding a non-conservative P17R substitution in the conserved repressor domain of ZNF34 protein-segregating completely with MDD in all available individuals in the family in which it was discovered. Further analysis showed a common ZNF34 coding indel segregating with MDD in a separate family, possibly indicating the presence of an unobserved, linked, rare variant in that particular family. Our results indicate that genes encoding transcription factors expressed in the brain might be an important group of MDD candidate genes and that rare variants in ZNF34 might contribute to susceptibility to MDD and perhaps other affective disorders.