Prospective biomarkers of major depressive disorder: a systematic review and meta-analysis.
Kennis Mitzy,Gerritsen Lotte,van Dalen Marije,Williams Alishia,Cuijpers Pim,Bockting Claudi
Leading biological hypotheses propose that biological changes may underlie major depressive disorder onset and relapse/recurrence. Here, we investigate if there is prospective evidence for biomarkers derived from leading theories. We focus on neuroimaging, gastrointestinal factors, immunology, neurotrophic factors, neurotransmitters, hormones, and oxidative stress. Searches were performed in Pubmed, Embase and PsychInfo for articles published up to 06/2019. References and citations of included articles were screened to identify additional articles. Inclusion criteria were having an MDD diagnosis as outcome, a biomarker as predictor, and prospective design search terms were formulated accordingly. PRISMA guidelines were applied. Meta-analyses were performed using a random effect model when three or more comparable studies were identified, using a random effect model. Our search resulted in 67,464 articles, of which 75 prospective articles were identified on: Neuroimaging (N = 24), Gastrointestinal factors (N = 1), Immunology (N = 8), Neurotrophic (N = 2), Neurotransmitters (N = 1), Hormones (N = 39), Oxidative stress (N = 1). Meta-analyses on brain volumes and immunology markers were not significant. Only cortisol (N = 19, OR = 1.294, p = 0.024) showed a predictive effect on onset/relapse/recurrence of MDD, but not on time until MDD onset/relapse/recurrence. However, this effect disappeared when studies including participants with a baseline clinical diagnosis were removed from the analyses. Other studies were too heterogeneous to compare. Thus, there is a lack of evidence for leading biological theories for onset and maintenance of depression. Only cortisol was identified as potential predictor for MDD, but results are influenced by the disease state. High-quality (prospective) studies on MDD are needed to disentangle the etiology and maintenance of MDD.
Neural Markers of Resilience in Adolescent Females at Familial Risk for Major Depressive Disorder.
Fischer Adina S,Camacho M Catalina,Ho Tiffany C,Whitfield-Gabrieli Susan,Gotlib Ian H
Importance:Adolescence is a neurodevelopmental period during which experience-dependent plasticity in brain circuitry may confer vulnerability to depression as well as resilience to disorder. Little is known, however, about the neural mechanisms that underlie resilience during this critical period of brain development. Objective:To examine neural functional connectivity correlates of resilience in adolescent females at high and low familial risk for depression who did and did not develop the disorder. Design, Setting, and Participants:A longitudinal study was conducted at Stanford University from October 1, 2003, to January 31, 2017. Sixty-five female adolescents participated in the study: 20 at high risk in whom depression did not develop (resilient), 20 at high risk in whom depression developed (converted), and 25 at low risk with no history of psychopathology (control). Main Outcomes and Measures:We compared functional connectivity between resilient and converted, and between resilient and control, adolescent females using voxelwise 2-sided t tests to examine neural markers of resilience to depression as the main outcomes of interest. Specifically, we assessed differences in connectivity of the limbic (amygdala seed), salience (anterior insula seed), and executive control (dorsolateral prefrontal cortex seed) networks, implicated in emotion regulation. We also examined the association between functional connectivity and life events. Results:Of the 65 participants (mean [SD] age, 18.9 [2.5] years), adolescent females in the resilient group had greater connectivity between the amygdala and orbitofrontal cortex (z score = 0.23; P < .001) and between the dorsolateral prefrontal cortex and frontotemporal regions (z score = 0.24; P < .001) than did converted adolescent females. In adolescent females in the resilient group only, strength of amygdala-orbitofrontal cortex connectivity was correlated with positive life events (r18 = 0.48; P = .03). Resilient adolescent females had greater connectivity within frontal (z score = 0.07; P < .001) and limbic (z score = 0.21; P < .001) networks than did control individuals. Both high-risk groups had greater salience network connectivity: the converted group had greater intranetwork connectivity than did the resilient (z score = 0.13; P < .001) and control (z score = 0.10; P < .001) groups, and the adolescent females in the resilient group had greater salience network connectivity with the superior frontal gyrus than did the converted (z score = 0.24; P < .001) adolescent females. Conclusions and Relevance:Resilient adolescent females have compensatory functional connectivity patterns in emotion regulatory networks that correlate with positive life events, suggesting that experience-dependent plasticity within these networks may confer resilience to depression. Further studies are warranted concerning connectivity-associated targets for promoting resilience in high-risk individuals.
Epigenetic Aging in Major Depressive Disorder.
Han Laura K M,Aghajani Moji,Clark Shaunna L,Chan Robin F,Hattab Mohammad W,Shabalin Andrey A,Zhao Min,Kumar Gaurav,Xie Lin Ying,Jansen Rick,Milaneschi Yuri,Dean Brian,Aberg Karolina A,van den Oord Edwin J C G,Penninx Brenda W J H
The American journal of psychiatry
OBJECTIVE:Major depressive disorder is associated with an increased risk of mortality and aging-related diseases. The authors examined whether major depression is associated with higher epigenetic aging in blood as measured by DNA methylation (DNAm) patterns, whether clinical characteristics of major depression have a further impact on these patterns, and whether the findings replicate in brain tissue. METHOD:DNAm age was estimated using all methylation sites in blood of 811 depressed patients and 319 control subjects with no lifetime psychiatric disorders and low depressive symptoms from the Netherlands Study of Depression and Anxiety. The residuals of the DNAm age estimates regressed on chronological age were calculated to indicate epigenetic aging. Major depression diagnosis and clinical characteristics were assessed with questionnaires and psychiatric interviews. Analyses were adjusted for sociodemographic characteristics, lifestyle, and health status. Postmortem brain samples of 74 depressed patients and 64 control subjects were used for replication. Pathway enrichment analysis was conducted using ConsensusPathDB to gain insight into the biological processes underlying epigenetic aging in blood and brain. RESULTS:Significantly higher epigenetic aging was observed in patients with major depression compared with control subjects (Cohen's d=0.18), with a significant dose effect with increasing symptom severity in the overall sample. In the depression group, epigenetic aging was positively and significantly associated with childhood trauma score. The case-control difference was replicated in an independent data set of postmortem brain samples. The top significantly enriched Gene Ontology terms included neuronal processes. CONCLUSIONS:As compared with control subjects, patients with major depression exhibited higher epigenetic aging in blood and brain tissue, suggesting that they are biologically older than their corresponding chronological age. This effect was even more profound in the presence of childhood trauma.
No Alterations of Brain Structural Asymmetry in Major Depressive Disorder: An ENIGMA Consortium Analysis.
de Kovel Carolien G F,Aftanas Lyubomir,Aleman André,Alexander-Bloch Aaron F,Baune Bernhard T,Brack Ivan,Bülow Robin,Busatto Filho Geraldo,Carballedo Angela,Connolly Colm G,Cullen Kathryn R,Dannlowski Udo,Davey Christopher G,Dima Danai,Dohm Katharina,Erwin-Grabner Tracy,Frodl Thomas,Fu Cynthia H Y,Hall Geoffrey B,Glahn David C,Godlewska Beata,Gotlib Ian H,Goya-Maldonado Roberto,Grabe Hans Jörgen,Groenewold Nynke A,Grotegerd Dominik,Gruber Oliver,Harris Mathew A,Harrison Ben J,Hatton Sean N,Hickie Ian B,Ho Tiffany C,Jahanshad Neda,Kircher Tilo,Krämer Bernd,Krug Axel,Lagopoulos Jim,Leehr Elisabeth J,Li Meng,MacMaster Frank P,MacQueen Glenda,McIntosh Andrew M,McLellan Quinn,Medland Sarah E,Mueller Bryon A,Nenadic Igor,Osipov Evgeny,Papmeyer Martina,Portella Maria J,Reneman Liesbeth,Rosa Pedro G P,Sacchet Matthew D,Schnell Knut,Schrantee Anouk,Sim Kang,Simulionyte Egle,Sindermann Lisa,Singh Aditya,Stein Dan J,Ubani Benjamin N,Van der Wee Nic J A,Van der Werff Steven J A,Veer Ilya M,Vives-Gilabert Yolanda,Völzke Henry,Walter Henrik,Walter Martin,Schreiner Melinda Westlund,Whalley Heather,Winter Nils,Wittfeld Katharina,Yang Tony T,Yüksel Dilara,Zaremba Dario,Thompson Paul M,Veltman Dick J,Schmaal Lianne,Francks Clyde
The American journal of psychiatry
OBJECTIVE:Asymmetry is a subtle but pervasive aspect of the human brain, and it may be altered in several psychiatric conditions. MRI studies have shown subtle differences of brain anatomy between people with major depressive disorder and healthy control subjects, but few studies have specifically examined brain anatomical asymmetry in relation to this disorder, and results from those studies have remained inconclusive. At the functional level, some electroencephalography studies have indicated left fronto-cortical hypoactivity and right parietal hypoactivity in depressive disorders, so aspects of lateralized anatomy may also be affected. The authors used pooled individual-level data from data sets collected around the world to investigate differences in laterality in measures of cortical thickness, cortical surface area, and subcortical volume between individuals with major depression and healthy control subjects. METHODS:The authors investigated differences in the laterality of thickness and surface area measures of 34 cerebral cortical regions in 2,256 individuals with major depression and 3,504 control subjects from 31 separate data sets, and they investigated volume asymmetries of eight subcortical structures in 2,540 individuals with major depression and 4,230 control subjects from 32 data sets. T-weighted MRI data were processed with a single protocol using FreeSurfer and the Desikan-Killiany atlas. The large sample size provided 80% power to detect effects of the order of Cohen's d=0.1. RESULTS:The largest effect size (Cohen's d) of major depression diagnosis was 0.085 for the thickness asymmetry of the superior temporal cortex, which was not significant after adjustment for multiple testing. Asymmetry measures were not significantly associated with medication use, acute compared with remitted status, first episode compared with recurrent status, or age at onset. CONCLUSIONS:Altered brain macro-anatomical asymmetry may be of little relevance to major depression etiology in most cases.
Assessment of Striatal Dopamine Transporter Binding in Individuals With Major Depressive Disorder: In Vivo Positron Emission Tomography and Postmortem Evidence.
Pizzagalli Diego A,Berretta Sabina,Wooten Dustin,Goer Franziska,Pilobello Kanoelani T,Kumar Poornima,Murray Laura,Beltzer Miranda,Boyer-Boiteau Anne,Alpert Nathanial,El Fakhri Georges,Mechawar Naguib,Vitaliano Gordana,Turecki Gustavo,Normandin Marc
Importance:Major depressive disorder (MDD) might involve dopamine (DA) reductions. The DA transporter (DAT) regulates DA clearance and neurotransmission and is sensitive to DA levels, with preclinical studies (including those involving inescapable stressors) showing that DAT density decreases when DA signaling is reduced. Despite preclinical data, evidence of reduced DAT in MDD is inconclusive. Objective:Using a highly selective DAT positron emission tomography (PET) tracer ([11C] altropane), DAT availability was probed in individuals with MDD who were not taking medication. Levels of DAT expression were also evaluated in postmortem tissues from donors with MDD who died by suicide. Design, Setting, and Participants:This cross-sectional PET study was conducted at McLean Hospital (Belmont, Massachusetts) and Massachusetts General Hospital (Boston) and enrolled consecutive individuals with MDD who were not taking medication and demographically matched healthy controls between January 2012 and March 2014. Brain tissues were obtained from the Douglas-Bell Canada Brain Bank. For the PET component, 25 individuals with current MDD who were not taking medication and 23 healthy controls recruited from McLean Hospital were included (all provided usable data). For the postmortem component, 15 individuals with depression and 14 healthy controls were considered. Intervention:PET scan. Main Outcomes and Measures:Striatal and midbrain DAT binding potential was assessed. For the postmortem component, tyrosine hydroxylase and DAT levels were evaluated using Western blots. Results:Compared with 23 healthy controls (13 women [56.5%]; mean [SD] age, 26.49 [7.26] years), 25 individuals with MDD (19 women [76.0%]; mean [SD] age, 26.52 [5.92] years) showed significantly lower in vivo DAT availability in the bilateral putamen and ventral tegmental area (Cohen d range, -0.62 to -0.71), and both reductions were exacerbated with increasing numbers of depressive episodes. Unlike healthy controls, the MDD group failed to show an age-associated reduction in striatal DAT availability, with young individuals with MDD being indistinguishable from older healthy controls. Moreover, DAT availability in the ventral tegmental area was lowest in individuals with MDD who reported feeling trapped in stressful circumstances. Lower DAT levels (and tyrosine hydroxylase) in the putamen of MDD compared with healthy controls were replicated in postmortem analyses (Cohen d range, -0.92 to -1.15). Conclusions and Relevance:Major depressive disorder, particularly with recurring episodes, is characterized by decreased striatal DAT expression, which might reflect a compensatory downregulation due to low DA signaling within mesolimbic pathways.
Intrinsic connectomes are a predictive biomarker of remission in major depressive disorder.
Korgaonkar Mayuresh S,Goldstein-Piekarski Andrea N,Fornito Alexander,Williams Leanne M
Although major depressive disorder (MDD) is associated with altered functional coupling between disparate neural networks, the degree to which such measures are ameliorated by antidepressant treatment is unclear. It is also unclear whether functional connectivity can be used as a predictive biomarker of treatment response. Here, we used whole-brain functional connectivity analysis to identify neural signatures of remission following antidepressant treatment, and to identify connectomic predictors of treatment response. 163 MDD and 62 healthy individuals underwent functional MRI during pre-treatment baseline and 8-week follow-up sessions. Patients were randomized to escitalopram, sertraline or venlafaxine-XR antidepressants and assessed at follow-up for remission. Baseline measures of intrinsic functional connectivity between each pair of 333 regions were analyzed to identify pre-treatment connectomic features that distinguish remitters from non-remitters. We then interrogated these connectomic differences to determine if they changed post-treatment, distinguished patients from controls, and were modulated by medication type. Irrespective of medication type, remitters were distinguished from non-remitters by greater connectivity within the default mode network (DMN); specifically, between the DMN, fronto-parietal and somatomotor networks, the DMN and visual, limbic, auditory and ventral attention networks, and between the fronto-parietal and somatomotor networks with cingulo-opercular and dorsal attention networks. This baseline hypo-connectivity for non-remitters also distinguished them from controls and increased following treatment. In contrast, connectivity for remitters was higher than controls at baseline and also following remission, suggesting a trait-like connectomic characteristic. Increased functional connectivity within and between large-scale intrinsic brain networks may characterize acute recovery with antidepressants in depression.
Polyunsaturated fatty acids metabolism, purine metabolism and inosine as potential independent diagnostic biomarkers for major depressive disorder in children and adolescents.
Zhou Xinyu,Liu Lanxiang,Lan Xinghui,Cohen David,Zhang Yuqing,Ravindran Arun V,Yuan Shuai,Zheng Peng,Coghill David,Yang Lining,Hetrick Sarah E,Jiang Xiaofeng,Benoliel Jean-Jacques,Cipriani Andrea,Xie Peng
Major depressive disorder (MDD) in children and adolescents is a recurrent and disabling condition globally but its pathophysiology remains poorly elucidated and there are limited effective treatments available. We performed metabolic profiling of plasma samples based on ultra-high-performance liquid chromatography equipped with quadrupole time-offlight mass spectrometry to explore the potential biomarkers of depression in children and adolescents with MDD. We identified several perturbed pathways, including fatty acid metabolism-particularly the polyunsaturated fatty acids metabolism, and purine metabolism-that were associated with MDD in these young patients. In addition, inosine was shown as a potential independent diagnostic biomarker for MDD, achieving an area under the ROC curve of 0.999 in discriminating drug-naive MDD patients and 0.866 in discriminating drug-treated MDD from healthy controls. Moreover, we found evidence for differences in the pathophysiology of MDD in children and adolescents to that of adult MDD, specifically with tryptophan metabolism. Through metabolomic analysis, we have identified links between a framework of metabolic perturbations and the pathophysiology and diagnostic biomarker of child and adolescent MDD.
Glutamatergic neurometabolite levels in major depressive disorder: a systematic review and meta-analysis of proton magnetic resonance spectroscopy studies.
Alterations in glutamatergic neurotransmission are implicated in the pathophysiology of depression, and the glutamatergic system represents a treatment target for depression. To summarize the nature of glutamatergic alterations in patients with depression, we conducted a meta-analysis of proton magnetic resonance (H-MRS) spectroscopy studies examining levels of glutamate. We used the search terms: depress* AND (MRS OR "magnetic resonance spectroscopy"). The search was performed with MEDLINE, Embase, and PsycINFO. The inclusion criteria were H-MRS studies comparing levels of glutamate + glutamine (Glx), glutamate, or glutamine between patients with depression and healthy controls. Standardized mean differences (SMD) were calculated to assess group differences in the levels of glutamatergic neurometabolites. Forty-nine studies met the eligibility criteria, which included 1180 patients and 1066 healthy controls. There were significant decreases in Glx within the medial frontal cortex (SMD = -0.38; 95% CI, -0.69 to -0.07) in patients with depression compared with controls. Subanalyses revealed that there was a significant decrease in Glx in the medial frontal cortex in medicated patients with depression (SMD = -0.50; 95% CI, -0.80 to -0.20), but not in unmedicated patients (SMD = -0.27; 95% CI, -0.76 to 0.21) compared with controls. Overall, decreased levels of glutamatergic metabolites in the medial frontal cortex are linked with the pathophysiology of depression. These findings are in line with the hypothesis that depression may be associated with abnormal glutamatergic neurotransmission.
Association of translocator protein total distribution volume with duration of untreated major depressive disorder: a cross-sectional study.
Setiawan Elaine,Attwells Sophia,Wilson Alan A,Mizrahi Romina,Rusjan Pablo M,Miler Laura,Xu Cynthia,Sharma Sarita,Kish Stephen,Houle Sylvain,Meyer Jeffrey H
The lancet. Psychiatry
BACKGROUND:People with major depressive disorder frequently exhibit increasing persistence of major depressive episodes. However, evidence for neuroprogression (ie, increasing brain pathology with longer duration of illness) is scarce. Microglial activation, which is an important component of neuroinflammation, is implicated in neuroprogression. We examined the relationship of translocator protein (TSPO) total distribution volume (V), a marker of microglial activation, with duration of untreated major depressive disorder, and with total illness duration and antidepressant exposure. METHODS:In this cross-sectional study, we recruited participants aged 18-75 years from the Toronto area and the Centre for Addiction and Mental Health (Toronto, ON, Canada). Participants either had major depressive episodes secondary to major depressive disorder or were healthy, as confirmed with a structured clinical interview and consultation with a study psychiatrist. To be enrolled, participants with major depressive episodes had to score a minimum of 17 on the 17-item Hamilton Depression Rating Scale, and had to be medication free or taking a stable dose of medication for at least 4 weeks before PET scanning. Eligible participants were non-smokers; had no history of or concurrent alcohol or substance dependence, neurological illness, autoimmune disorder, or severe medical problems; and were free from acute medical illnesses for the previous 2 weeks before PET scanning. Participants were excluded if they had used brain stimulation treatments within the 6 months before scanning, had used anti-inflammatory drugs lasting at least 1 week within the past month, were taking hormone replacement therapy, had psychotic symptoms, had bipolar disorder (type I or II) or borderline antisocial personality disorder, or were pregnant or breastfeeding. We scanned three primary grey-matter regions of interest (prefrontal cortex, anterior cingulate cortex, and insula) and 12 additional regions and subregions using F-FEPPA PET to measure TSPO V. We investigated the duration of untreated major depressive disorder, and the combination of total duration of disease and duration of antidepressant treatment, as predictor variables of TSPO V, assessing their significance. FINDINGS:Between Sept 1, 2009, and July 6, 2017, we screened 134 participants for eligibility, of whom 81 were included in the study (current major depressive episode n=51, healthy n=30). We excluded one participant with a major depressive episode from the analysis because of unreliable information about previous medication use. Duration of untreated major depressive disorder was a strong predictor of TSPO V (p<0·0001), as were total illness duration (p=0·0021) and duration of antidepressant exposure (p=0·037). The combination of these predictors accounted for about 50% of variance in TSPO V in the prefrontal cortex, anterior cingulate cortex, and insula. In participants who had untreated major depressive disorder for 10 years or longer, TSPO V was 29-33% greater in the prefrontal cortex, anterior cingulate cortex, and insula than in participants who were untreated for 9 years or less. TSPO V was also 31-39% greater in the three primary grey-matter regions of participants with long duration of untreated major depressive disorder compared with healthy participants (p=0·00047). INTERPRETATION:Microglial activation, as shown by TSPO V, is greater in patients with chronologically advanced major depressive disorder with long periods of no antidepressant treatment than in patients with major depressive disorder with short periods of no antidepressant treatment, which is strongly suggestive of a different illness phase. Consistent with this, the yearly increase in microglial activation is no longer evident when antidepressant treatment is given. FUNDING:Canadian Institutes of Health Research and Neuroscience Catalyst Fund.
Severity of current depression and remission status are associated with structural connectome alterations in major depressive disorder.
Repple Jonathan,Mauritz Marco,Meinert Susanne,de Lange Siemon C,Grotegerd Dominik,Opel Nils,Redlich Ronny,Hahn Tim,Förster Katharina,Leehr Elisabeth J,Winter Nils,Goltermann Janik,Enneking Verena,Fingas Stella M,Lemke Hannah,Waltemate Lena,Nenadic Igor,Krug Axel,Brosch Katharina,Schmitt Simon,Stein Frederike,Meller Tina,Jansen Andreas,Steinsträter Olaf,Baune Bernhard T,Kircher Tilo,Dannlowski Udo,van den Heuvel Martijn P
Major depressive disorder (MDD) is associated to affected brain wiring. Little is known whether these changes are stable over time and hence might represent a biological predisposition, or whether these are state markers of current disease severity and recovery after a depressive episode. Human white matter network ("connectome") analysis via network science is a suitable tool to investigate the association between affected brain connectivity and MDD. This study examines structural connectome topology in 464 MDD patients (mean age: 36.6 years) and 432 healthy controls (35.6 years). MDD patients were stratified categorially by current disease status (acute vs. partial remission vs. full remission) based on DSM-IV criteria. Current symptom severity was assessed continuously via the Hamilton Depression Rating Scale (HAMD). Connectome matrices were created via a combination of T1-weighted magnetic resonance imaging (MRI) and tractography methods based on diffusion-weighted imaging. Global tract-based metrics were not found to show significant differences between disease status groups, suggesting conserved global brain connectivity in MDD. In contrast, reduced global fractional anisotropy (FA) was observed specifically in acute depressed patients compared to fully remitted patients and healthy controls. Within the MDD patients, FA in a subnetwork including frontal, temporal, insular, and parietal nodes was negatively associated with HAMD, an effect remaining when correcting for lifetime disease severity. Therefore, our findings provide new evidence of MDD to be associated with structural, yet dynamic, state-dependent connectome alterations, which covary with current disease severity and remission status after a depressive episode.
The future of rodent models in depression research.
Gururajan Anand,Reif Andreas,Cryan John F,Slattery David A
Nature reviews. Neuroscience
Currently, over 300 million people worldwide have depression, and the socioeconomic burden of this debilitating disorder is anticipated to increase markedly over the coming decades against a background of increasing global turmoil. Despite this impending crisis, we are still waiting for improved therapeutic options for this disorder to emerge, which has led to increasing criticism of the role and value of preclinical models of depression. In this Review, we examine this landscape, focusing firstly on issues related to the terminology used in this context and the myriad of preclinical approaches to modelling and assaying aspects of depression in rodents. We discuss the importance of sex as a biological variable and the controversial idea of intergenerational and transgenerational transmission of depressive-like traits. We then examine the technical strategies available to dissect these models and review emerging evidence for putative druggable disease mechanisms. Finally, we propose a brief framework for future research that makes optimal use of these models and will, we hope, accelerate the discovery of improved antidepressants.
Man and the Microbiome: A New Theory of Everything?
Butler Mary I,Cryan John F,Dinan Timothy G
Annual review of clinical psychology
The gut microbiome is implicated in the pathophysiology of a wide range of psychological disorders. Preclinical studies have provided us with key insights into the mechanisms by which the microbiome influences bidirectional gut-brain communication. There are many signaling pathways involved, including the hypothalamic-pituitary-adrenal axis, immune modulation, tryptophan and serotonin metabolism, bile acid transformation, microbial production of neuroactive compounds, and regulation of the endocannabinoid system. The complex and widespread influence of the microbiome on many physiological and psychological processes has generated a keen interest in its therapeutic potential for depression, anxiety, autism, and other psychiatric disorders. It has been shown that the microbiome composition of people suffering with such conditions differs significantly from that of healthy controls, and although the area is in its infancy, interventional studies that alter a person's microbiome through the use of probiotics, prebiotics, or dietary change can alleviate psychopathological symptoms.
Depression and obesity: evidence of shared biological mechanisms.
Depression and obesity are common conditions with major public health implications that tend to co-occur within individuals. The relationship between these conditions is bidirectional: the presence of one increases the risk for developing the other. It has thus become crucial to gain a better understanding of the mechanisms responsible for the intertwined downward physiological spirals associated with both conditions. The present review focuses specifically on shared biological pathways that may mechanistically explain the depression-obesity link, including genetics, alterations in systems involved in homeostatic adjustments (HPA axis, immuno-inflammatory activation, neuroendocrine regulators of energy metabolism including leptin and insulin, and microbiome) and brain circuitries integrating homeostatic and mood regulatory responses. Furthermore, the review addresses interventional opportunities and questions to be answered by future research that will enable a comprehensive characterization and targeting of the biological links between depression and obesity.
Programming Bugs: Microbiota and the Developmental Origins of Brain Health and Disease.
Codagnone Martin G,Spichak Simon,O'Mahony Siobhain M,O'Leary Olivia F,Clarke Gerard,Stanton Catherine,Dinan Timothy G,Cryan John F
It has been nearly 30 years since Dr. David Barker first highlighted the importance of prenatal factors in contributing to the developmental origins of adult disease. This concept was later broadened to include postnatal events. It is clear that the interaction between genetic predisposition and early life environmental exposures is key in this regard. However, recent research has also identified another important factor in the microbiota-the trillions of microorganisms that inhabit key body niches, including the vagina and gastrointestinal tract. Because the composition of these maternal microbiome sites has been linked to maternal metabolism and is also vertically transmitted to offspring, changes in the maternal microbiota are poised to significantly affect the newborn. In fact, several lines of evidence show that the gut microbiota interacts with diet, drugs, and stress both prenatally and postnatally and that these exogenous factors could also affect the dynamic changes in the microbiota composition occurring during pregnancy. Animal models have shown great utility in illuminating how these disruptions result in behavioral and brain morphological phenotypes reminiscent of psychiatric disorders (anxiety, depression, schizophrenia, and autism spectrum disorders). Increasing evidence points to critical interactions among the microbiota, host genetics, and both the prenatal and postnatal environments to temporally program susceptibility to psychiatric disorders later in life. Sex-specific phenotypes may be programmed through the influence of the microbiota on the hypothalamic-pituitary-adrenal axis and neuroimmune system.
Gut microbiota modulate neurobehavior through changes in brain insulin sensitivity and metabolism.
Soto Marion,Herzog Clémence,Pacheco Julian A,Fujisaka Shiho,Bullock Kevin,Clish Clary B,Kahn C Ronald
Obesity and diabetes in humans are associated with increased rates of anxiety and depression. To understand the role of the gut microbiome and brain insulin resistance in these disorders, we evaluated behaviors and insulin action in brain of mice with diet-induced obesity (DIO) with and without antibiotic treatment. We find that DIO mice have behaviors reflective of increased anxiety and depression. This is associated with decreased insulin signaling and increased inflammation in in the nucleus accumbens and amygdala. Treatment with oral metronidazole or vancomycin decreases inflammation, improves insulin signaling in the brain and reduces signs of anxiety and depression. These effects are associated with changes in the levels of tryptophan, GABA, BDNF, amino acids, and multiple acylcarnitines, and are transferable to germ-free mice by fecal transplant. Thus, changes in gut microbiota can control brain insulin signaling and metabolite levels, and this leads to altered neurobehaviors.
The neuroactive potential of the human gut microbiota in quality of life and depression.
The relationship between gut microbial metabolism and mental health is one of the most intriguing and controversial topics in microbiome research. Bidirectional microbiota-gut-brain communication has mostly been explored in animal models, with human research lagging behind. Large-scale metagenomics studies could facilitate the translational process, but their interpretation is hampered by a lack of dedicated reference databases and tools to study the microbial neuroactive potential. Surveying a large microbiome population cohort (Flemish Gut Flora Project, n = 1,054) with validation in independent data sets (n = 1,070), we studied how microbiome features correlate with host quality of life and depression. Butyrate-producing Faecalibacterium and Coprococcus bacteria were consistently associated with higher quality of life indicators. Together with Dialister, Coprococcus spp. were also depleted in depression, even after correcting for the confounding effects of antidepressants. Using a module-based analytical framework, we assembled a catalogue of neuroactive potential of sequenced gut prokaryotes. Gut-brain module analysis of faecal metagenomes identified the microbial synthesis potential of the dopamine metabolite 3,4-dihydroxyphenylacetic acid as correlating positively with mental quality of life and indicated a potential role of microbial γ-aminobutyric acid production in depression. Our results provide population-scale evidence for microbiome links to mental health, while emphasizing confounder importance.
Depression's Unholy Trinity: Dysregulated Stress, Immunity, and the Microbiome.
Cruz-Pereira Joana S,Rea Kieran,Nolan Yvonne M,O'Leary Olivia F,Dinan Timothy G,Cryan John F
Annual review of psychology
Depression remains one of the most prevalent psychiatric disorders, with many patients not responding adequately to available treatments. Chronic or early-life stress is one of the key risk factors for depression. In addition, a growing body of data implicates chronic inflammation as a major player in depression pathogenesis. More recently, the gut microbiota has emerged as an important regulator of brain and behavior and also has been linked to depression. However, how this holy trinity of risk factors interact to maintain physiological homeostasis in the brain and body is not fully understood. In this review, we integrate the available data from animal and human studies on these three factors in the etiology and progression of depression. We also focus on the processes by which this microbiota-immune-stress matrix may influence centrally mediated events and on possible therapeutic interventions to correct imbalances in this triune.
Adverse Childhood Experiences: Implications for Offspring Telomere Length and Psychopathology.
Esteves Kyle C,Jones Christopher W,Wade Mark,Callerame Keegan,Smith Alicia K,Theall Katherine P,Drury Stacy S
The American journal of psychiatry
OBJECTIVE:Adverse childhood experiences (ACEs) are associated with mental and physical health risks that, through biological and psychosocial pathways, likely span generations. Within an individual, telomere length (TL), an established marker of cellular stress and aging, is associated with both ACE exposure and psychopathology, providing the basis for an emerging literature suggesting that TL is a biomarker of the health risks linked to early-life adversity both within and across generations. The authors tested the effect of maternal ACEs on both the trajectory of infant TL and infant social-emotional problems at 18 months of age. METHODS:Pregnant women were recruited, and maternal scores on the Adverse Childhood Experience questionnaire were obtained, along with demographic and prenatal stress measures. Postnatal visits with 155 mother-infant dyads occurred when infants were 4, 12, and 18 months of age. At each visit, infant buccal swabs were collected for TL measurement, and mothers completed measures of maternal depression. Mothers also completed the Child Behavior Checklist at the 18-month visit. Mixed-effects modeling was used to test how maternal ACEs influenced infant TL trajectory. Linear regression was used to test the association between maternal ACEs and infant internalizing and externalizing behaviors. Finally, the interaction between telomere attrition from 4 to 18 months and maternal ACEs was examined as a predictor of infant scores on the Child Behavior Checklist. RESULTS:Higher maternal ACEs were associated with shorter infant TL across infancy and higher infant externalizing behavioral problems at 18 months. No associations were found with internalizing behavioral problems. Telomere attrition from 4 to 18 months interacted with maternal ACEs to predict externalizing behaviors. In infants whose mothers reported higher scores on the Adverse Childhood Experience questionnaire, greater telomere attrition predicted higher externalizing problems, even when accounting for maternal postnatal depression and prenatal stress. CONCLUSIONS:These data demonstrate an interactive pathway between maternal early-life adversity and infant TL that predicts emerging behavioral problems in the next generations.
Predicting Suicide Attempts and Suicide Deaths Following Outpatient Visits Using Electronic Health Records.
The American journal of psychiatry
OBJECTIVE:The authors sought to develop and validate models using electronic health records to predict suicide attempt and suicide death following an outpatient visit. METHOD:Across seven health systems, 2,960,929 patients age 13 or older (mean age, 46 years; 62% female) made 10,275,853 specialty mental health visits and 9,685,206 primary care visits with mental health diagnoses between Jan. 1, 2009, and June 30, 2015. Health system records and state death certificate data identified suicide attempts (N=24,133) and suicide deaths (N=1,240) over 90 days following each visit. Potential predictors included 313 demographic and clinical characteristics extracted from records for up to 5 years before each visit: prior suicide attempts, mental health and substance use diagnoses, medical diagnoses, psychiatric medications dispensed, inpatient or emergency department care, and routinely administered depression questionnaires. Logistic regression models predicting suicide attempt and death were developed using penalized LASSO (least absolute shrinkage and selection operator) variable selection in a random sample of 65% of the visits and validated in the remaining 35%. RESULTS:Mental health specialty visits with risk scores in the top 5% accounted for 43% of subsequent suicide attempts and 48% of suicide deaths. Of patients scoring in the top 5%, 5.4% attempted suicide and 0.26% died by suicide within 90 days. C-statistics (equivalent to area under the curve) for prediction of suicide attempt and suicide death were 0.851 (95% CI=0.848, 0.853) and 0.861 (95% CI=0.848, 0.875), respectively. Primary care visits with scores in the top 5% accounted for 48% of subsequent suicide attempts and 43% of suicide deaths. C-statistics for prediction of suicide attempt and suicide death were 0.853 (95% CI=0.849, 0.857) and 0.833 (95% CI=0.813, 0.853), respectively. CONCLUSIONS:Prediction models incorporating both health record data and responses to self-report questionnaires substantially outperform existing suicide risk prediction tools.
Severity and Variability of Depression Symptoms Predicting Suicide Attempt in High-Risk Individuals.
Importance:Predicting suicidal behavior continues to be among the most challenging tasks in psychiatry. Objectives:To examine the trajectories of clinical predictors of suicide attempt (specifically, depression symptoms, hopelessness, impulsivity, aggression, impulsive aggression, and irritability) for their ability to predict suicide attempt and to compute a risk score for suicide attempts. Design, Setting, and Participants:This is a longitudinal study of the offspring of parents (or probands) with mood disorders who were recruited from inpatient units at Western Psychiatric Institute and Clinic (Pittsburgh) and New York State Psychiatric Institute. Participants were recruited from July 15, 1997, to September 6, 2005, and were followed up through January 21, 2014. Probands and offspring (n = 663) were interviewed at baseline and at yearly follow-ups for 12 years. Lifetime and current psychiatric disorders were assessed, and self-reported questionnaires were administered. Model evaluation used 10-fold cross-validation, which split the entire data set into 10 equal parts, fit the model to 90% of the data (training set), and assessed it on the remaining 10% (test set) and repeated that process 10 times. Preliminary analyses were performed from July 20, 2015, to October 5, 2016. Additional analyses were conducted from July 26, 2017, to July 24, 2018. Main Outcomes and Measures:The broad definition of suicide attempt included actual, interrupted, and aborted attempts as well as suicidal ideation that prompted emergency referrals during the study. The narrow definition referred to actual attempt only. Results:The sample of offspring (n = 663) was almost equally distributed by sex (316 female [47.7%]) and had a mean (SD) age of 23.8 (8.5) years at the time of censored observations. Among the 663 offspring, 71 (10.7%) had suicide attempts over the course of the study. The trajectory of depression symptoms with the highest mean scores and variability over time was the only trajectory to predict suicide attempt (odds ratio [OR], 4.72; 95% CI, 1.47-15.21; P = .01). In addition, we identified the following predictors: younger age (OR, 0.82; 95% CI, 0.74-0.90; P < .001), lifetime history of unipolar disorder (OR, 4.71; 95% CI, 1.63-13.58; P = .004), lifetime history of bipolar disorder (OR, 3.4; 95% CI, 0.96-12.04; P = .06), history of childhood abuse (OR, 2.98; 95% CI, 1.40-6.38; P = .01), and proband actual attempt (OR, 2.24; 95% CI, 1.06-4.75; P = .04). Endorsing a score of 3 or higher on the risk score tool resulted in high sensitivity (87.3%) and moderate specificity (63%; area under the curve = 0.80). Conclusions and Relevance:The specific predictors of suicide attempt identified are those that clinicians already assess during routine psychiatric evaluations; monitoring and treating depression symptoms to reduce their severity and fluctuation may attenuate the risk for suicidal behavior.
Pretreatment Rostral Anterior Cingulate Cortex Theta Activity in Relation to Symptom Improvement in Depression: A Randomized Clinical Trial.
Pizzagalli Diego A,Webb Christian A,Dillon Daniel G,Tenke Craig E,Kayser Jürgen,Goer Franziska,Fava Maurizio,McGrath Patrick,Weissman Myrna,Parsey Ramin,Adams Phil,Trombello Joseph,Cooper Crystal,Deldin Patricia,Oquendo Maria A,McInnis Melvin G,Carmody Thomas,Bruder Gerard,Trivedi Madhukar H
Importance:Major depressive disorder (MDD) remains challenging to treat. Although several clinical and demographic variables have been found to predict poor antidepressant response, these markers have not been robustly replicated to warrant implementation in clinical care. Increased pretreatment rostral anterior cingulate cortex (rACC) theta activity has been linked to better antidepressant outcomes. However, no prior study has evaluated whether this marker has incremental predictive validity over clinical and demographic measures. Objective:To determine whether increased pretreatment rACC theta activity would predict symptom improvement regardless of randomization arm. Design, Setting, and Participants:A multicenter randomized clinical trial enrolled outpatients without psychosis and with chronic or recurrent MDD between July 29, 2011, and December 15, 2015 (Establishing Moderators and Biosignatures of Antidepressant Response for Clinical Care [EMBARC]). Patients were consecutively recruited from 4 university hospitals: 634 patients were screened, 296 were randomized to receive sertraline hydrochloride or placebo, 266 had electroencephalographic (EEG) recordings, and 248 had usable EEG data. Resting EEG data were recorded at baseline and 1 week after trial onset, and rACC theta activity was extracted using source localization. Intent-to-treat analysis was conducted. Data analysis was performed from October 7, 2016, to January 19, 2018. Interventions:An 8-week course of sertraline or placebo. Main Outcomes and Measures:The 17-item Hamilton Rating Scale for Depression score (assessed at baseline and weeks 1, 2, 3, 4, 6, and 8). Results:The 248 participants (160 [64.5%] women, 88 [35.5%] men) with usable EEG data had a mean (SD) age of 36.75 (13.15) years. Higher rACC theta activity at both baseline (b = -1.05; 95% CI, -1.77 to -0.34; P = .004) and week 1 (b = -0.83; 95% CI, -1.60 to -0.06; P < .04) predicted greater depressive symptom improvement, even when controlling for clinical and demographic variables previously linked with treatment outcome. These effects were not moderated by treatment arm. The rACC theta marker, in combination with clinical and demographic variables, accounted for an estimated 39.6% of the variance in symptom change (with 8.5% of the variance uniquely attributable to the rACC theta marker). Conclusions and Relevance:Increased pretreatment rACC theta activity represents a nonspecific prognostic marker of treatment outcome. This is the first study to date to demonstrate that rACC theta activity has incremental predictive validity. Trial Registration:clinicaltrials.gov Identifier: NCT01407094.
Neural Indicators of Anhedonia: Predictors and Mechanisms of Treatment Change in a Randomized Clinical Trial in Early Childhood Depression.
Barch Deanna M,Whalen Diana,Gilbert Kirsten,Kelly Danielle,Kappenman Emily S,Hajcak Greg,Luby Joan L
BACKGROUND:Early childhood depression is associated with anhedonia and reduced event-related potential (ERP) responses to rewarding or pleasant stimuli. Whether these neural measures are indicators of target engagement or treatment outcome is not yet known. METHODS:We measured ERP responses to win and loss feedback in a guessing task and to pleasant versus neutral pictures in young (4.0-6.9 years of age) depressed children before and after randomization to either 18 weeks of Parent-Child Interaction Therapy-Emotion Development (PCIT-ED) treatment or waitlist (WL) control condition. RESULTS:Analyses included reward positivity (RewP) data from 118 children randomized to PCIT-ED treatment (n = 60) or WL control condition (n = 58) at baseline and late positive potential (LPP) data from 99 children (44 PCIT-ED treatment vs. 55 WL control condition) at baseline. Children in the PCIT-ED group showed a greater reduction in anhedonia (F = 10.32, p = .002, partial η = .09). RewP reward responses increased more (F = 5.45, p = .02, partial η = .06) for PCIT-ED and a greater change in RewP was associated with a greater reduction in major depressive disorder symptoms (r = -.24, p = .05). Baseline RewP did not predict treatment change. LPPs to positive pictures did not change across treatment, but greater baseline LPPs to positive pictures predicted a higher likelihood of remission from major depressive disorder in the PCIT-ED group (B = 0.14; SE = 0.07; odds ratio = 1.15; p = .03). CONCLUSIONS:The ERP reward response improved in young children with depression during a treatment designed to enhance emotion development, providing evidence of target engagement of the neural systems associated with reward. Further, greater baseline LPP responses to positive pictures were associated with a greater reduction in depression, suggesting that this ERP measure can predict which children are most likely to respond to treatment.
A methylation study of long-term depression risk.
Recurrent and chronic major depressive disorder (MDD) accounts for a substantial part of the disease burden because this course is most prevalent and typically requires long-term treatment. We associated blood DNA methylation profiles from 581 MDD patients at baseline with MDD status 6 years later. A resampling approach showed a highly significant association between methylation profiles in blood at baseline and future disease status (P = 2.0 × 10). Top MWAS results were enriched specific pathways, overlapped with genes found in GWAS of MDD disease status, autoimmune disease and inflammation, and co-localized with eQTLS and (genic enhancers of) of transcription sites in brain and blood. Many of these findings remained significant after correction for multiple testing. The major themes emerging were cellular responses to stress and signaling mechanisms linked to immune cell migration and inflammation. This suggests that an immune signature of treatment-resistant depression is already present at baseline. We also created a methylation risk score (MRS) to predict MDD status 6 years later. The AUC of our MRS was 0.724 and higher than risk scores created using a set of five putative MDD biomarkers, genome-wide SNP data, and 27 clinical, demographic and lifestyle variables. Although further studies are needed to examine the generalizability to different patient populations, these results suggest that methylation profiles in blood may present a promising avenue to support clinical decision making by providing empirical information about the likelihood MDD is chronic or will recur in the future.
Genetics of response to cognitive behavior therapy in adults with major depression: a preliminary report.
Major depressive disorder is heritable and a leading cause of disability. Cognitive behavior therapy is an effective treatment for major depression. By quantifying genetic risk scores based on common genetic variants, the aim of this report was to explore the utility of psychiatric and cognitive trait genetic risk scores, for predicting the response of 894 adults with major depressive disorder to cognitive behavior therapy. The participants were recruited in a psychiatric setting, and the primary outcome score was measured using the Montgomery Åsberg Depression Rating Scale-Self Rated. Single-nucleotide polymorphism genotyping arrays were used to calculate the genomic risk scores based on large genetic studies of six phenotypes: major depressive disorder, bipolar disorder, attention-deficit/hyperactivity disorder, autism spectrum disorder, intelligence, and educational attainment. Linear mixed-effect models were used to test the relationships between the six genetic risk scores and cognitive behavior therapy outcome. Our analyses yielded one significant interaction effect (B = 0.09, p < 0.001): the autism spectrum disorder genetic risk score correlated with Montgomery Åsberg Depression Rating Scale-Self Rated changes during treatment, and the higher the autism spectrum disorder genetic load, the less the depressive symptoms decreased over time. The genetic risk scores for the other psychiatric and cognitive traits were not related to depressive symptom severity or change over time. Our preliminary results indicated, as expected, that the genomics of the response of patients with major depression to cognitive behavior therapy were complex and that future efforts should aim to maximize sample size and limit subject heterogeneity in order to gain a better understanding of the use of genetic risk factors to predict treatment outcome.
Irritability and Its Clinical Utility in Major Depressive Disorder: Prediction of Individual-Level Acute-Phase Outcomes Using Early Changes in Irritability and Depression Severity.
Jha Manish K,Minhajuddin Abu,South Charles,Rush A John,Trivedi Madhukar H
The American journal of psychiatry
OBJECTIVE:The authors evaluated improvement in irritability with antidepressant treatment and its prognostic utility in treatment-seeking adult outpatients with major depressive disorder. METHODS:Mixed-model analyses were used to assess changes in irritability (as measured with the five-item irritability domain of the Concise Associated Symptom Tracking [CAST-IRR] scale) from baseline to week 4 after controlling for depression severity (as measured with the 16-item Quick Inventory of Depressive Symptomatology-Clinician Rated [QIDS-C]) in the Combining Medications to Enhance Depression Outcomes (CO-MED) trial (N=664). An interactive calculator for remission (QIDS-C score ≤5) and no meaningful benefit (<30% reduction in QIDS-C score from baseline) at week 8 was developed with logistic regression analyses in the CO-MED trial using participants with complete data (N=431) and independently replicated in the Suicide Assessment and Methodology Study (SAMS) (N=163). RESULTS:In the CO-MED trial, irritability was significantly reduced (effect size=1.06) from baseline to week 4, and this reduction remained significant after adjusting for QIDS-C change (adjusted effect size=0.36). A one-standard-deviation greater reduction in CAST-IRR score from baseline to week 4 predicted a 1.73 times higher likelihood of remission and a 0.72 times lower likelihood of no meaningful benefit at week 8, independent of baseline QIDS-C and CAST-IRR scores and reduction in QIDS-C score from baseline to week 4. The model estimates for remission (area under the curve [AUC]=0.79) and no meaningful benefit (AUC=0.76) in the CO-MED trial were used to predict remission (AUC=0.80) and no meaningful benefit (AUC=0.84) in SAMS and to develop an interactive calculator. CONCLUSIONS:Irritability is an important symptom domain of major depressive disorder that is not fully reflected in depressive symptom severity measures. Early reductions in irritability, when combined with changes in depressive symptom severity, provide a robust estimate of likelihood of remission or no meaningful benefit in outpatients with major depression.
Sexual violence against children in South Africa: a nationally representative cross-sectional study of prevalence and correlates.
Ward Catherine L,Artz Lillian,Leoschut Lezanne,Kassanjee Reshma,Burton Patrick
The Lancet. Global health
BACKGROUND:We aimed to complete a nationally representative study of sexual violence against children in South Africa, and its correlates, since we could identify no other such study. METHODS:For this nationally representative, cross-sectional study in South Africa, households were selected by use of a multistage sampling frame, stratified by province, urban or rural setting, and race group, and schools were selected on the basis that they were closest to the area in which households were selected. Interviews and self-administered questionnaires in each location inquired into lifetime and last-year prevalence of sexual abuse, and its correlates among children aged 15-17 years, whose parents gave informed consent and they themselves gave informed assent. FINDINGS:The final household sample was 5631 (94·6% participation rate). 9·99% (95% CI 8·65-11·47) of boys and 14·61% (95% CI 12·83-16·56) of girls reported some lifetime sexual victimisation. Physical abuse, emotional abuse, neglect, family violence, and other victimisations were all strongly associated with sexual victimisation. The following were associated with greater risk of sexual abuse (adjusted odds ratio [OR]); school enrolment (OR 2·12, 95% CI 1·29-3·48); rural dwelling (0·59; 0·43-0·80); having a flush toilet (1·43, 1·04-1·96); parental substance misuse (2·37, 1·67-3·36); being disabled (1·42, 1·10-1·82); female (but not male) caregivers' poor knowledge of the child's whereabouts, friends, and activities (1·07, 0·75-1·53) and poor quality of the relationship with the child (ie, poor acceptance; 1·20, 0·55-2·60). The child's own substance misuse (4·72, 3·73-5·98) and high-risk sexual behaviour (3·71, 2·99-4·61) were the behaviours most frequently associated with sexual abuse, with mental health conditions found to be less prevalent than these factors but still strongly associated with sexual victimisation (post-traumatic stress disorder 2·81, 1·65-4·78; depression 3·43, 2·26-5·19; anxiety 2·48, 1·61-3·81). INTERPRETATION:Sexual violence is widespread among both girls and boys, and is associated with serious health problems. Associated factors require multisectoral responses to prevent sexual violence or mitigate consequences. FUNDING:UBS Optimus Foundation.
Association of Neuroimaging Measures of Emotion Processing and Regulation Neural Circuitries With Symptoms of Bipolar Disorder in Offspring at Risk for Bipolar Disorder.
Acuff Heather E,Versace Amelia,Bertocci Michele A,Ladouceur Cecile D,Hanford Lindsay C,Manelis Anna,Monk Kelly,Bonar Lisa,McCaffrey Alicia,Goldstein Benjamin I,Goldstein Tina R,Sakolsky Dara,Axelson David,Birmaher Boris,Phillips Mary L,
Importance:Bipolar disorder (BD) is difficult to distinguish from other psychiatric disorders. Neuroimaging studies can identify objective markers of BD risk. Objective:To identify neuroimaging measures in emotion processing and regulation neural circuitries and their associations with symptoms specific to youth at risk for BD. Design, Setting, and Participants:This cross-sectional (August 1, 2011, to July 31, 2017) and longitudinal (February 1, 2013, to November 30, 2017) neuroimaging study performed at the University of Pittsburgh Medical Center compared a sample of 31 offspring of parents with BD (OBP) with 28 offspring of comparison parents with non-BD psychopathologies (OCP) and 21 offspring of healthy parents (OHP); OBP, OCP, and OHP were recruited from the Bipolar Offspring Study and the Longitudinal Assessment of Manic Symptoms Study. Main Outcomes and Measures:Group differences in activity and functional connectivity during emotional face processing and n-back task performance in amygdala, dorsolateral and ventrolateral prefrontal cortices (PFC), caudal anterior cingulate cortices (cACC), and rostral anterior cingulate cortices (rACC) neuroimaging measures showing between-group differences and symptom severity (anxiety, affective lability, depression, mania). We hypothesized that elevated amygdala activity and/or lower PFC activity and abnormal amygdala to PFC functional connectivity would distinguish OBP from OCP and OHP, and magnitudes of these abnormalities would positively correlate with elevated symptom severity. We explored associations between changes in neuroimaging and symptom measures over follow-up (mean [SD], 2.9 [1.4] years) in a subset of participants (n = 30). Results:Eighty participants were included (mean [SD] age, 14.2 (2.1) years; 35 female). Twelve neuroimaging measures explained 51% of the variance in the results of neuroimaging measures overall. Of the 12, 9 showed significant main associations of the group; however, after post hoc analyses and Bonferroni corrections, only 7 showed statistically significant associations between groups (corrected P < .05 for all). Of the 7, 2 showed significant relationships with symptoms. Offspring of parents with BD had greater right rACC activity when regulating attention to happy faces vs OCP (mean [SD] difference, 0.744 [0.249]; 95% CI, 0.134-1.354; P = .01), which positively correlated with affective lability severity (ρ = 0.304; uncorrected P = .006). Offspring of parents with BD had greater amygdala to left cACC functional connectivity when regulating attention to fearful faces vs OCP (mean [SD] difference, 0.493 [0.169]; 95% CI, 0.079-0.908; P = .01). Increases in this measure positively correlated with increases in affective lability over follow-up (r = 0.541; P = .003). Conclusions and Relevance:Greater anterior cingulate cortex activity and functional connectivity during emotion regulation tasks may be specific markers of BD risk. These findings highlight potential neural targets to aid earlier identification of and guide new treatment developments for BD.
Factors associated with depression in patients with type 2 diabetes in the Gaza Strip: a cross sectional study.
Saman Khaled Abu,Massad Salwa,Ibaid Ali Abu,Anan Huda,Daher Mamhoud,Salman Rand,Aldeqes Saleh
Lancet (London, England)
BACKGROUND:About 9% of the world's population has diabetes. Most people with diabetes live in developing countries. Diabetes is the fourth leading cause of death in the occupied Palestinian territory. The likelihood of diabetes complications increases with depression. Worldwide, about half of patients with diabetes have severe depression that has been misidentified by health providers. The aim of this study was to examine factors associated with depression in patients with type 2 diabetes in the Gaza governorate. METHODS:This cross-sectional study included patients attending three primary health centres in 2016. A convenient purposive approach to sampling was used to select three centres from the 15 centres in the Gaza governorate, covering the east (border), middle, and west areas. Since 2014, all patients with type 2 diabetes have been screened for depression using the Patient Health Questionnaire 9. Data on demographic, socioeconomic, and health status and on patients' beliefs were collected during interviews with structured questionnaires, and medical data were collected from patient records. χ tests and logistic regression were used to test associations between dependent and independent variables. FINDINGS:380 patients were included in the study. 255 participants were women with type 2 diabetes and older than 40 years. The median age of participants was 59 years (IQR 13). 285 (75%) participants were married, and 221 (58%) had not completed high school. 103 (27%) participants screened positive for depression. Factors positively associated with depression were age (people younger than 50 years were at greater risk than people aged 50 years and older [odds ratio 2·25, 95% CI 1·2-4·2]), being single (2·04, 1·68-3·55), not believing that they can manage the disease (2·9, 1·6-5·6), and living in border areas (3·6, 2·0-6·2). INTERPRETATION:More attention should be given to young, single patients and to those living in border areas. Treatment options and care for patients with depression should be strengthened with counselling and medications. FUNDING:Palestinian National Institute of Public Health.
Carotid Artery Stiffness and Incident Depressive Symptoms: The Paris Prospective Study III.
van Sloten Thomas T,Boutouyrie Pierre,Tafflet Muriel,Offredo Lucile,Thomas Frédérique,Guibout Catherine,Climie Rachel E,Lemogne Cédric,Pannier Bruno,Laurent Stéphane,Jouven Xavier,Empana Jean-Philippe
BACKGROUND:Arterial stiffness may contribute to late-life depression via cerebral microvascular damage, but evidence is scarce. No longitudinal study has evaluated the association between arterial stiffness and risk of depressive symptoms. Therefore, we investigated the association between carotid artery stiffness and incident depressive symptoms in a large community-based cohort study. METHODS:This longitudinal study included 7013 participants (mean age 59.7 ± 6.3 years; 35.8% women) free of depressive symptoms at baseline. Carotid artery stiffness (high-resolution echo tracking) was determined at baseline. Presence of depressive symptoms was determined at baseline and at 4 and 6 years of follow-up, and was defined as a score ≥7 on the validated Questionnaire of Depression, Second Version, Abridged and/or new use of antidepressant medication. Logistic regression and generalized estimating equations were used. RESULTS:In total, 6.9% (n = 484) of the participants had incident depressive symptoms. Individuals in the lowest tertile of carotid distensibility coefficient (indicating greater carotid artery stiffness) compared with those in the highest tertile had a higher risk of incident depressive symptoms (odds ratio: 1.43; 95% confidence interval: 1.10-1.87), after adjustment for age, sex, living alone, education, lifestyle, cardiovascular risk factors, and baseline Questionnaire of Depression, Second Version, Abridged scores. Results were qualitatively similar when we used carotid Young's elastic modulus as a measure of carotid stiffness instead of carotid distensibility coefficient, and when we used generalized estimating equations instead of logistic regression. CONCLUSIONS:Greater carotid stiffness is associated with a higher incidence of depressive symptoms. This supports the hypothesis that carotid stiffness may contribute to the development of late-life depression.
Maternal prenatal depressive symptoms and risk for early-life psychopathology in offspring: genetic analyses in the Norwegian Mother and Child Birth Cohort Study.
Hannigan Laurie J,Eilertsen Espen Moen,Gjerde Line C,Reichborn-Kjennerud Ted,Eley Thalia C,Rijsdijk Fruhling V,Ystrom Eivind,McAdams Tom A
The lancet. Psychiatry
BACKGROUND:Maternal prenatal depression is a known risk factor for early-life psychopathology among offspring; however, potential risk transmission mechanisms need to be distinguished. We aimed to test the relative importance of passive genetic transmission, direct exposure, and indirect exposure in the association between maternal prenatal depressive symptoms and early-life internalising and externalising psychopathology in offspring. METHODS:We used structural equation modelling of phenotypic data and genetically informative relationships from the families of participants in the Norwegian Mother and Child Birth Cohort Study (MoBa). The analytic subsample of MoBa used in the current study comprises 22 195 mothers and 35 299 children. We used mothers' self-reported depressive symptoms during pregnancy, as captured by the Symptom Checklist, and their reports of symptoms of psychopathology in their offspring during the first few years of life (measured at 18, 36, and 60 months using the Child Behavior Checklist). FINDINGS:Maternal prenatal depressive symptoms were found to be associated with early-life psychopathology primarily via intergenerationally shared genetic factors, which explained 41% (95% CI 36-46) of variance in children's internalising problems and 37% (30-44) of variance in children's externalising problems. For internalising problems, phenotypic transmission also contributed significantly, accounting for 14% (95% CI 5-19) of the association, but this contribution was found to be explained by exposure to concurrent maternal depressive symptoms, rather than by direct exposure in utero. INTERPRETATION:Associations between maternal prenatal depressive symptoms and offspring behavioural outcomes in early childhood are likely to be at least partially explained by shared genes. This genetic confounding should be considered when attempting to quantify risks posed by in-utero exposure to maternal depressive symptoms. FUNDING:UK Economic and Social Research Council, Norwegian Research Council, Norwegian Ministries of Health and Care Services, and Education & Research, Wellcome Trust, Royal Society, and National Institute for Health Research.
Adverse Childhood Experiences and the Risk of Diabetes: Examining the Roles of Depressive Symptoms and Cardiometabolic Dysregulations in the Whitehall II Cohort Study.
Deschênes Sonya S,Graham Eva,Kivimäki Mika,Schmitz Norbert
OBJECTIVE:Adverse childhood experiences (ACEs) are associated with an increased risk of diabetes in adulthood. However, the potential mediating roles of depression and cardiometabolic dysregulations in this association are not clear. RESEARCH DESIGN AND METHODS:Prospective data were from the Whitehall II cohort study, with the phase 5 assessment (1997-1999) serving as baseline ( = 5,093, age range = 44-68 years, 27.3% female). ACEs were retrospectively reported at phase 5. Depressive symptoms (Center for Epidemiologic Studies Depression Scale) and cardiometabolic dysregulations (inflammation, central obesity, HDL cholesterol, triglycerides, impaired fasting glucose, and hypertension) were examined at phase 7 (2002-2004). Incident diabetes was examined at phases 8-11 (2006-2013) via self-report and blood samples. Participants reporting diabetes prior to phase 8 were excluded. Statistical mediation was examined with path analysis using structural equation modeling. ACEs were modeled as an observed continuous variable, whereas depressive symptoms and cardiometabolic dysregulations were modeled as latent variables. Unstandardized probit regression coefficients with 95% CI are reported for mediation analysis. RESULTS:ACEs were associated with an increased likelihood of diabetes, with every addition of ACE associated with an ∼11% increase in odds of diabetes (odds ratio 1.11 [95% CI 1.00, 1.24], = 0.048). In mediation analysis, ACEs were indirectly associated with diabetes via depressive symptoms (indirect effect 0.03 [95% CI 0.02, 0.04], < 0.001) and cardiometabolic dysregulations (indirect effect 0.03 [95% CI 0.01, 0.05], = 0.03). CONCLUSIONS:This study provides further evidence of the detrimental psychological and physiological effects of ACEs and suggests that depression and cardiometabolic dysregulations may be pathways linking ACEs with diabetes in adulthood.
Early Intervention in Bipolar Disorder.
Vieta Eduard,Salagre Estela,Grande Iria,Carvalho André F,Fernandes Brisa S,Berk Michael,Birmaher Boris,Tohen Mauricio,Suppes Trisha
The American journal of psychiatry
Bipolar disorder is a recurrent disorder that affects more than 1% of the world population and usually has its onset during youth. Its chronic course is associated with high rates of morbidity and mortality, making bipolar disorder one of the main causes of disability among young and working-age people. The implementation of early intervention strategies may help to change the outcome of the illness and avert potentially irreversible harm to patients with bipolar disorder, as early phases may be more responsive to treatment and may need less aggressive therapies. Early intervention in bipolar disorder is gaining momentum. Current evidence emerging from longitudinal studies indicates that parental early-onset bipolar disorder is the most consistent risk factor for bipolar disorder. Longitudinal studies also indicate that a full-blown manic episode is often preceded by a variety of prodromal symptoms, particularly subsyndromal manic symptoms, therefore supporting the existence of an at-risk state in bipolar disorder that could be targeted through early intervention. There are also identifiable risk factors that influence the course of bipolar disorder, some of them potentially modifiable. Valid biomarkers or diagnosis tools to help clinicians identify individuals at high risk of conversion to bipolar disorder are still lacking, although there are some promising early results. Pending more solid evidence on the best treatment strategy in early phases of bipolar disorder, physicians should carefully weigh the risks and benefits of each intervention. Further studies will provide the evidence needed to finish shaping the concept of early intervention. AJP AT 175 Remembering Our Past As We Envision Our Future April 1925: Interpretations of Manic-Depressive Phases Earl Bond and G.E. Partridge reviewed a number of patients with manic-depressive illness in search of a unifying endo-psychic conflict. They concluded that understanding either phase of illness was "elusive" and "tantalizing beyond reach." (Am J Psychiatry 1925: 81: 643-662 ).
Early Variations in White Matter Microstructure and Depression Outcome in Adolescents With Subthreshold Depression.
Vulser Hélène,Paillère Martinot Marie-Laure,Artiges Eric,Miranda Ruben,Penttilä Jani,Grimmer Yvonne,van Noort Betteke M,Stringaris Argyris,Struve Maren,Fadai Tahmine,Kappel Viola,Goodman Robert,Tzavara Eleni,Massaad Charbel,Banaschewski Tobias,Barker Gareth J,Bokde Arun L W,Bromberg Uli,Brühl Rüdiger,Büchel Christian,Cattrell Anna,Conrod Patricia,Desrivières Sylvane,Flor Herta,Frouin Vincent,Gallinat Juergen,Garavan Hugh,Gowland Penny,Heinz Andreas,Nees Frauke,Papadopoulos-Orfanos Dimitri,Paus Tomas,Poustka Luise,Rodehacke Sarah,Smolka Michael N,Walter Henrik,Whelan Robert,Schumann Gunter,Martinot Jean-Luc,Lemaitre Hervé,
The American journal of psychiatry
OBJECTIVE:White matter microstructure alterations have recently been associated with depressive episodes during adolescence, but it is unknown whether they predate depression. The authors investigated whether subthreshold depression in adolescence is associated with white matter microstructure variations and whether they relate to depression outcome. METHOD:Adolescents with subthreshold depression (N=96) and healthy control subjects (N=336) drawn from a community-based cohort were compared using diffusion tensor imaging and whole brain tract-based spatial statistics (TBSS) at age 14 to assess white matter microstructure. They were followed up at age 16 to assess depression. Probabilistic tractography was used to reconstruct white matter streamlines spreading from the regions identified in the TBSS analysis and along bundles implicated in emotion regulation, the uncinate fasciculus and the cingulum. The authors searched for mediating effects of white matter microstructure on the relationship between baseline subthreshold depression and depression at follow-up, and then explored the specificity of the findings. RESULTS:Lower fractional anisotropy (FA) and higher radial diffusivity were found in the anterior corpus callosum in the adolescents with subthreshold depression. Tractography analysis showed that they also had lower FA in the right cingulum streamlines, along with lower FA and higher mean diffusivity in tracts connecting the corpus callosum to the anterior cingulate cortex. The relation between subthreshold depression at baseline and depression at follow-up was mediated by FA values in the latter tracts, and lower FA values in those tracts distinctively predicted higher individual risk for depression. CONCLUSIONS:Early FA variations in tracts projecting from the corpus callosum to the anterior cingulate cortex may denote a higher risk of transition to depression in adolescents.
Longitudinal Associations Among Bullying by Peers, Disordered Eating Behavior, and Symptoms of Depression During Adolescence.
Importance:Bullying by peers has been associated with disordered eating behavior and symptoms of depression among adolescents as both an antecedent and an outcome. Identification of the temporal pattern of associations among bullying by peers, disordered eating behavior, and depression in adolescence is needed for the optimal targeting of intervention and prevention. Objective:To assess the concurrent and longitudinal associations among bullying by peers, disordered eating behavior, and symptoms of depression using a cascade model that controlled for within-time and across-time (ie, stability paths) associations while examining cross-lag effects. Design, Setting, and Participants:In this 5-year longitudinal cohort study, 612 participants of the McMaster Teen Study were included. This ongoing Canadian study examines the associations among bullying, mental health, and educational outcomes. Data collection began in 2008 when students were in grade 5 (10 years of age) and have since been collected annually. Data analysis was performed between August 20 and October 18, 2017. Exposures:Bullying by peers was assessed in grades 7 to 11 using a composite measure of 5 items. Main Outcomes and Measures:Disordered eating behavior was assessed in grades 7 to 11 using the Short Screen for Eating Disorders, and depressive symptoms were assessed in grades 7 to 11 using the Behavior Assessment System for Children-Second Edition. Results:The 612 students included in the analytic sample had a mean age (SD) of 13.03 (0.38) years in grade 7; 331 (54.1%) were girls and 392 (71.1%) were white. Bullying by peers was concurrently associated with disordered eating behavior and depressive symptoms at every time point during the 5-year period (r range [SE], 0.15-0.48 [0.04-0.08]; P < .01). Disordered eating behavior was associated longitudinally with depressive symptoms at every time point (β range [SE], 0.14-0.19 [0.06-0.08]; P < .02) and bullying by peers at 2 time points (β range [SE], 0.12-0.22 [0.06-0.07]; P < .04) in girls and boys. Conclusions and Relevance:Bullying by peers was proximally associated with multiple psychopathologic symptoms, whereas symptoms of disordered eating behavior were a key risk factor for future depressive symptoms and bullying by peers. Interventions aimed at reducing problematic eating behavior in adolescents may attenuate the risk of future depressive symptoms and relational problems.
The Burden of Bereavement: Early-Onset Depression and Impairment in Youths Bereaved by Sudden Parental Death in a 7-Year Prospective Study.
Pham Steven,Porta Giovanna,Biernesser Candice,Walker Payne Monica,Iyengar Satish,Melhem Nadine,Brent David A
The American journal of psychiatry
OBJECTIVE:The authors sought to determine the long-term impact of sudden parental death on youths and pathways between youth bereavement and impairment. METHODS:Youths (N=216) who lost a parent to suicide, accident, or sudden natural death and nonbereaved youths (N=172) were followed periodically for up to 7 years. The incidence and prevalence of disorder and of functional impairment, as well as pathways to impairment, were assessed using Cox and mixed-effects logistic regression and structural equation modeling. RESULTS:Prior to parental death, bereaved youths had higher rates of psychiatric disorder, parental psychiatric disorder, and maltreatment. Even after adjustment for predeath risk factors, bereavement was associated with an increased incidence of depression, posttraumatic stress disorder, and functional impairment. The peak incidence of depression was in the first 2 years postbereavement, with incident depression occurring mainly in those who lost a parent at age 12 or younger. Youths bereaved by all three causes of death showed higher rates of impairment at all time points. Structural equation modeling found that bereavement had a direct effect on impairment and was also linked to impairment via its effects on early and later depression and through negative life events. Child psychiatric disorder prior to parental loss also contributed to functional impairment. CONCLUSIONS:Parental death increased the incidence of depression in offspring early in the course of bereavement. Early identification and treatment of depression in bereaved youths and augmentation of family resilience may protect against later sequelae of functional impairment.
Association of Depression With Mortality in Older Adults Undergoing Transcatheter or Surgical Aortic Valve Replacement.
Drudi Laura M,Ades Matthew,Turkdogan Sena,Huynh Caroline,Lauck Sandra,Webb John G,Piazza Nicolo,Martucci Giuseppe,Langlois Yves,Perrault Louis P,Asgar Anita W,Labinaz Marino,Lamy Andre,Noiseux Nicolas,Peterson Mark D,Arora Rakesh C,Lindman Brian R,Bendayan Melissa,Mancini Rita,Trnkus Amanda,Kim Dae H,Popma Jeffrey J,Afilalo Jonathan
Importance:Depression is increasingly recognized as a risk factor for adverse outcomes in cardiovascular disease. However, little is known about depression in older adults undergoing transcatheter (TAVR) or surgical (SAVR) aortic valve replacement. Objective:To determine the prevalence of depression and its association with all-cause mortality in older adults undergoing TAVR or SAVR. Design, Setting, and Participants:This preplanned analysis of the Frailty Aortic Valve Replacement (FRAILTY-AVR) prospective cohort study included 14 centers in 3 countries from November 15, 2011, through April 7, 2016. Individuals 70 years or older who underwent TAVR or SAVR were enrolled. Depressive symptoms were evaluated using the Geriatric Depression Scale Short Form at baseline and follow-up. Main Outcomes and Measures:All-cause mortality at 1 and 12 months after TAVR or SAVR. Logistic regression was used to determine the association of depression with mortality after adjusting for confounders such as frailty and cognitive impairment. Results:Among 1035 older adults (427 men [41.3%] and 608 women [58.7%]) with a mean (SD) age of 81.4 (6.1) years, 326 (31.5%) had a positive result of screening for depression, whereas only 89 (8.6%) had depression documented in their clinical record. After adjusting for clinical and geriatric confounders, baseline depression was found to be associated with mortality at 1 month (odds ratio [OR], 2.20; 95% CI, 1.18-4.10) and at 12 months (OR, 1.532; 95% CI, 1.03-2.24). Persistent depression, defined as baseline depression that was still present 6 months after the procedure, was associated with a 3-fold increase in mortality at 12 months (OR, 2.98; 95% CI, 1.08-8.20). Conclusions and Relevance:One in 3 older adults undergoing TAVR or SAVR had depressive symptoms at baseline and a higher risk of short-term and midterm mortality. Patients with persistent depressive symptoms at follow-up had the highest risk of mortality.
Sources of Parent-Offspring Resemblance for Major Depression in a National Swedish Extended Adoption Study.
Kendler Kenneth S,Ohlsson Henrik,Sundquist Kristina,Sundquist Jan
Importance:Twin studies have assessed sibling resemblance for major depression (MD) but cannot address sources of resemblance across generations. Objective:To clarify the relative importance of genetic and rearing effects on the parent-offspring resemblance for MD. Design:This Swedish population register-based study examined parents and children from the following 5 family types: intact (2 041 816 offspring), adoptive (14 104 offspring), not-lived-with (NLW) father (116 601 offspring), stepfather (67 826 offspring), and triparental (29 205 offspring). The 5 family types permitted quantification of parent-offspring resemblance for genes plus rearing, genes-only, and rearing-only associations. Treated MD was assessed from national primary care, specialist care, and inpatient registries. Data were collected from January 1, 1960, through December 31, 2016. Exposure:Diagnosis of MD vs no diagnosis in parents. Main Outcomes and Measures:Registration for MD. Results:The study population included 2 269 552 offspring (51.5% male and 48.5% female; median age, 42; range, 26-56 years). The weighted tetrachoric correlations for MD across family types and across mothers and fathers were r = 0.17 (95% CI, 0.16-0.17) for genes plus rearing, r = 0.08 (95% CI, 0.06-0.09) for genes-only, and r = 0.08 (95% CI, 0.07-0.09) for rearing-only parent-child associations. Only the genes plus rearing association differed significantly between mothers (weighted tetrachoric correlation, r = 0.18; 95% CI, 0.18-0.18) and fathers (weighted tetrachoric correlation, r = 0.15; 95% CI, 0.15-0.16). In triparental families, the parent-offspring correlations for MD were estimated at r = 0.19 (95% CI, 0.17-0.22) for mothers in the genes plus rearing association, r = 0.10 (95% CI, 0.07-0.13) for NLW fathers in the genes-only association, and r = 0.08 (95% CI, 0.05-0.11) for stepfathers in the rearing-only association. In adoptive families, the effect of affected biological and affected adoptive parents on adoptee risk for MD was additive. In intact families, parental MD diagnosed by specialists in hospital or outpatient settings and primary care physicians affected equally the risk for MD in offspring. Conclusions and Relevance:The parent-offspring resemblance for treated MD arises from genetic factors and rearing experiences to an approximately equal extent. Both forms of cross-generational transmission act additively on the risk for MD in the offspring.
The Emergent Course of Bipolar Disorder: Observations Over Two Decades From the Canadian High-Risk Offspring Cohort.
Duffy Anne,Goodday Sarah,Keown-Stoneman Charles,Grof Paul
The American journal of psychiatry
OBJECTIVE:The authors sought to describe the emergent course of bipolar disorder in offspring of affected parents subgrouped by parental response to lithium prophylaxis. METHODS:Parent bipolar disorder was confirmed by the best-estimate procedure and lithium response by research protocol. High-risk offspring (N=279) and control subjects (N=87) were blindly assessed, annually on average, with the Kiddie Schedule for Affective Disorders and Schizophrenia-Present and Lifetime version or the Schedule for Affective Disorders and Schizophrenia-Lifetime version. DSM-IV diagnoses were confirmed using the best-estimate procedure in blind consensus reviews. Cumulative incidence and median age at onset were determined for lifetime syndrome- and symptom-level data. Mixed models assessed the association between parent and offspring course. A multistate model was used to estimate the clinical trajectory into bipolar disorder. RESULTS:The cumulative incidence of bipolar disorder was 24.5%, and the median age at onset was 20.7 years (range, 12.4 to 30.3). The clinical course of the affected parent was associated with that of the affected child. Depressive episodes predominated during the early bipolar course, especially among offspring of lithium responders. Childhood sleep and anxiety disorders significantly predicted 1.6-fold and 1.8-fold increases in risk of mood disorder, respectively, and depressive and manic symptoms predicted 2.7-fold and 2.3-fold increases in risk, respectively. The best-fit model of emerging bipolar disorder was a progressive sequence from nonspecific childhood antecedents to adolescent depression to index manic or hypomanic episode. Subthreshold sleep symptoms were significantly associated with transition from well to non-mood disorder, and psychotic symptoms in mood episodes were significantly associated with transition from unipolar to bipolar disorder. CONCLUSIONS:Bipolar disorder in individuals at familial risk typically unfolds in a progressive clinical sequence. Childhood sleep and anxiety disorders are important predictors, as are clinically significant mood symptoms and psychotic symptoms in depressive episodes.
Association of Midlife Cardiorespiratory Fitness With Incident Depression and Cardiovascular Death After Depression in Later Life.
Willis Benjamin L,Leonard David,Barlow Carolyn E,Martin Scott B,DeFina Laura F,Trivedi Madhukar H
Importance:Cardiorespiratory fitness (hereinafter referred to as fitness) as estimated by exercise testing is a modifiable risk factor independently associated with chronic diseases, cardiovascular disease (CVD) events, and mortality, but the association of fitness at midlife with incidence of later-life depression and the risk of CVD mortality after a depression diagnosis is unknown. Objective:To determine whether fitness measured in midlife would be inversely associated with later-life CVD mortality with antecedent depression. Design, Setting, and Participants:This retrospective cohort study at a single-center, community-based preventive medicine clinic was performed as part of the Cooper Center Longitudinal Study. Data were collected from January 13, 1971, through December 31, 2009, and analyzed from October 6, 2015, through August 14, 2017. Participants included generally healthy men and women who presented for preventive medicine examinations at midlife and who were eligible for Medicare from 1999 to 2010. Those with a self-reported history of depression, myocardial infarction, or stroke at examination were excluded. Exposures:Objective midlife fitness estimated from results of treadmill exercise testing. Main Outcomes and Measures:Depression diagnosis from Medicare claims files using established algorithms and CVD mortality from National Death Index records. Results:A total of 17 989 participants (80.2% men) with a mean (SD) age of 50.0 (8.7) years were included. After 117 218 person-years of Medicare follow-up, 2701 depression diagnoses, 610 deaths due to CVD without prior depression, and 231 deaths due to CVD after depression were observed. A high level of fitness in midlife was associated with a 16% lower risk of depression (hazard ratio [HR], 0.84; 95% CI, 0.74-0.95) compared with a low level of fitness. A high fitness level was also associated with a 61% lower risk of death due to CVD without depression (HR, 0.39; 95% CI, 0.31-0.48) compared with a low level of fitness. After a diagnosis of depression, a high fitness level was associated with a 56% lower risk of death due to CVD (HR, 0.44; 95% CI, 0.31-0.64) compared with a low fitness level. Conclusions and Relevance:Midlife fitness is associated with a lower risk of later-life depression, CVD mortality, and CVD mortality after incident later-life depression. These findings suggest the importance of midlife fitness in primary prevention of depression and subsequent CVD mortality in older age and should encourage physicians to consider fitness and physical activity in promoting healthy aging.
Efficacy and Safety of Intranasal Esketamine for the Rapid Reduction of Symptoms of Depression and Suicidality in Patients at Imminent Risk for Suicide: Results of a Double-Blind, Randomized, Placebo-Controlled Study.
Canuso Carla M,Singh Jaskaran B,Fedgchin Maggie,Alphs Larry,Lane Rosanne,Lim Pilar,Pinter Christine,Hough David,Sanacora Gerard,Manji Husseini,Drevets Wayne C
The American journal of psychiatry
OBJECTIVE:The authors compared the efficacy of standard-of-care treatment plus intranasal esketamine or placebo for rapid reduction of symptoms of major depression, including suicidality, among individuals at imminent suicide risk. METHOD:In a double-blind, multicenter, proof-of-concept study, 68 participants were randomly assigned to receive esketamine (84 mg) or placebo twice weekly for 4 weeks, in addition to comprehensive standard-of-care treatment. The primary efficacy endpoint was change in score from baseline to 4 hours after initial dose on the Montgomery-Åsberg Depression Rating Scale (MADRS). Clinician global judgment of suicide risk (from the Suicide Ideation and Behavior Assessment Tool) was also assessed. Secondary endpoints included these measures at 24 hours and double-blind endpoint at day 25. RESULTS:A significantly greater improvement in MADRS score was observed in the esketamine group compared with the placebo group at 4 hours (least-square mean difference=-5.3, SE=2.10; effect size=0.61) and at ∼24 hours (least-square mean difference=-7.2, SE=2.85; effect size=0.65), but not at day 25 (least-square mean difference=-4.5, SE=3.14; effect size=0.35). Significantly greater improvement was also observed in the esketamine group on the MADRS suicidal thoughts item score at 4 hours (effect size=0.67), but not at 24 hours (effect size=0.35) or at day 25 (effect size=0.29). Between-group reductions in clinician global judgment of suicide risk scores were not statistically different at any time point. The most common adverse events among participants in the esketamine group were nausea, dizziness, dissociation, unpleasant taste, and headache. CONCLUSIONS:These preliminary findings indicate that intranasal esketamine compared with placebo, given in addition to comprehensive standard-of-care treatment, may result in significantly rapid improvement in depressive symptoms, including some measures of suicidal ideation, among depressed patients at imminent risk for suicide.
The Genetic Epidemiology of Treated Major Depression in Sweden.
Kendler Kenneth S,Ohlsson Henrik,Lichtenstein Paul,Sundquist Jan,Sundquist Kristina
The American journal of psychiatry
OBJECTIVE:The authors examined the heritability of treated major depression in a twin and full/half-sibling design, to describe key genetic epidemiological features of major depression and to determine which clinical indices of genetic liability optimally predict risk of depression in relatives. METHOD:The authors examined all treated cases of major depression in Sweden recorded in inpatient, specialist, and primary care registries and, using OpenMx, estimated the etiologic role of genetic and environmental factors from monozygotic and dizygotic twin pairs and full and half siblings reared together and apart (total N=1,718,863 pairs). Eight indices of genetic risk were examined in 875,010 proband-relative pairs. RESULTS:The heritability of major depression in men and women was estimated at 0.41 (95% CI=0.21, 0.49) and 0.49 (95% CI=0.31, 0.56), respectively, in the twin design and 0.36 (95% CI=0.31, 0.38) and 0.51 (95% CI=0.51, 0.53), respectively, in the independent full/half-sibling design. The best estimate of the correlation in genetic effects across sexes was 0.89 (95% CI=0.87, 0.91). The results also showed evidence of modest shared environmental effects (0.02-0.05). Seven of the eight indices predicted risk for major depression in relatives, with stronger effects in those more closely related. The strongest indices were early age at onset, recurrence, comorbid anxiety disorder, and measures of clinical severity. CONCLUSIONS:In a large national sample, the heritability of major depression was similar when estimated from twin and full/half-sibling designs. The heritability of major depression was greater in women than in men, with the two sexes sharing most but not all genetic risk factors. In affected individuals, genetic risk for major depression could be meaningfully assessed from commonly available clinical indices.
Molecular Genetic Analysis Subdivided by Adversity Exposure Suggests Etiologic Heterogeneity in Major Depression.
Peterson Roseann E,Cai Na,Dahl Andy W,Bigdeli Tim B,Edwards Alexis C,Webb Bradley T,Bacanu Silviu-Alin,Zaitlen Noah,Flint Jonathan,Kendler Kenneth S
The American journal of psychiatry
OBJECTIVE:The extent to which major depression is the outcome of a single biological mechanism or represents a final common pathway of multiple disease processes remains uncertain. Genetic approaches can potentially identify etiologic heterogeneity in major depression by classifying patients on the basis of their experience of major adverse events. METHOD:Data are from the China, Oxford, and VCU Experimental Research on Genetic Epidemiology (CONVERGE) project, a study of Han Chinese women with recurrent major depression aimed at identifying genetic risk factors for major depression in a rigorously ascertained cohort carefully assessed for key environmental risk factors (N=9,599). To detect etiologic heterogeneity, genome-wide association studies, heritability analyses, and gene-by-environment interaction analyses were performed. RESULTS:Genome-wide association studies stratified by exposure to adversity revealed three novel loci associated with major depression only in study participants with no history of adversity. Significant gene-by-environment interactions were seen between adversity and genotype at all three loci, and 13.2% of major depression liability can be attributed to genome-wide interaction with adversity exposure. The genetic risk in major depression for participants who reported major adverse life events (27%) was partially shared with that in participants who did not (73%; genetic correlation=+0.64). Together with results from simulation studies, these findings suggest etiologic heterogeneity within major depression as a function of environmental exposures. CONCLUSIONS:The genetic contributions to major depression may differ between women with and those without major adverse life events. These results have implications for the molecular dissection of major depression and other complex psychiatric and biomedical diseases.
Healthy dietary indices and risk of depressive outcomes: a systematic review and meta-analysis of observational studies.
Lassale Camille,Batty G David,Baghdadli Amaria,Jacka Felice,Sánchez-Villegas Almudena,Kivimäki Mika,Akbaraly Tasnime
With depression being the psychiatric disorder incurring the largest societal costs in developed countries, there is a need to gather evidence on the role of nutrition in depression, to help develop recommendations and guide future psychiatric health care. The aim of this systematic review was to synthesize the link between diet quality, measured using a range of predefined indices, and depressive outcomes. Medline, Embase and PsychInfo were searched up to 31 May 2018 for studies that examined adherence to a healthy diet in relation to depressive symptoms or clinical depression. Where possible, estimates were pooled using random effect meta-analysis with stratification by observational study design and dietary score. A total of 20 longitudinal and 21 cross-sectional studies were included. These studies utilized an array of dietary measures, including: different measures of adherence to the Mediterranean diet, the Healthy Eating Index (HEI) and Alternative HEI (AHEI), the Dietary Approaches to Stop Hypertension, and the Dietary Inflammatory Index. The most compelling evidence was found for the Mediterranean diet and incident depression, with a combined relative risk estimate of highest vs. lowest adherence category from four longitudinal studies of 0.67 (95% CI 0.55-0.82). A lower Dietary Inflammatory Index was also associated with lower depression incidence in four longitudinal studies (relative risk 0.76; 95% CI: 0.63-0.92). There were fewer longitudinal studies using other indices, but they and cross-sectional evidence also suggest an inverse association between healthy diet and depression (e.g., relative risk 0.65; 95% CI 0.50-0.84 for HEI/AHEI). To conclude, adhering to a healthy diet, in particular a traditional Mediterranean diet, or avoiding a pro-inflammatory diet appears to confer some protection against depression in observational studies. This provides a reasonable evidence base to assess the role of dietary interventions to prevent depression. This systematic review was registered in the PROSPERO International Prospective Register of Systematic Reviews under the number CRD42017080579.
Efficacy of Transdermal Estradiol and Micronized Progesterone in the Prevention of Depressive Symptoms in the Menopause Transition: A Randomized Clinical Trial.
Gordon Jennifer L,Rubinow David R,Eisenlohr-Moul Tory A,Xia Kai,Schmidt Peter J,Girdler Susan S
Importance:The menopause transition and early postmenopausal period are associated with a 2- to 4-fold increased risk for clinically significant depressive symptoms. Although a few studies suggest that hormone therapy can effectively manage existing depression during this time, to our knowledge, there have been no studies testing whether hormone therapy can prevent the onset of perimenopausal and early postmenopausal depressive symptoms. Objective:To examine the efficacy of transdermal estradiol plus intermittent micronized progesterone (TE+IMP) in preventing depressive symptom onset among initially euthymic perimenopausal and early postmenopausal women. A secondary aim was to identify baseline characteristics predicting TE+IMP's beneficial mood effects. Design, Setting, and Participants:Double-blind, placebo-controlled randomized trial at the University of North Carolina at Chapel Hill from October 2010 to February 2016. Participants included euthymic perimenopausal and early postmenopausal women from the community, aged 45 to 60 years. Interventions:Transdermal estradiol (0.1 mg/d) or transdermal placebo for 12 months. Oral micronized progesterone (200 mg/d for 12 days) was also given every 3 months to women receiving active TE, and identical placebo pills were given to women receiving placebo. Main Outcome Measures:Scores on the Center for Epidemiological Studies-Depression Scale (CES-D), assessed at baseline and months 1, 2, 4, 6, 8, 10, and 12 after randomization, and the incidence of clinically significant depressive symptoms, defined as a CES-D score of at least 16. Results:Of 172 participants, 130 were white (76%), and 70 were African American (19%), with a mean household income of $50 000 to $79 999. The mean age was 51 years, and 43 developed clinically significant depressive symptoms. Women assigned to placebo were more likely than those assigned to TE+IMP to score at least 16 on the CES-D at least once during the intervention phase (32.3% vs 17.3%; odds ratio [OR], 2.5; 95% CI, 1.1-5.7; P = .03) and had a higher mean CES-D score across the intervention period (P = .03). Baseline reproductive stage moderated the effect of treatment (β, -1.97; SEM, 0.80; P for the interaction = .03) such that mood benefits of TE+IMP vs placebo were evident among women in the early menopause transition (β, -4.2; SEM, 1.2; P < .001) but not the late menopause transition (β, -0.9; SEM, 0.3; P = .23) or among postmenopausal women (β, -0.3; SEM, 1.1; P = .92). Stressful life events in the 6 months preceding enrollment also moderated the effect of treatment on mean CES-D score such that the mood benefits of TE+IMP increased with a greater number of events (β, 1.22; SEM, 0.40; P = .003). Baseline estradiol levels, baseline vasomotor symptoms, history of depression, and history of abuse did not moderate treatment effects. Conclusions:Twelve months of TE+IMP were more effective than placebo in preventing the development of clinically significant depressive symptoms among initially euthymic perimenopausal and early postmenopausal women. Trial Registration:clinicaltrials.gov Identifier: NCT01308814.
Association of Childhood Irritability and Depressive/Anxious Mood Profiles With Adolescent Suicidal Ideation and Attempts.
Orri Massimiliano,Galera Cedric,Turecki Gustavo,Forte Alberto,Renaud Johanne,Boivin Michel,Tremblay Richard E,Côté Sylvana M,Geoffroy Marie-Claude
Importance:Suicidal ideation and suicide attempt (suicidality) are common in adolescence and a public health concern. Childhood depression is a key risk factor for later suicidality and often co-occurs with irritability. No study to date has examined the joint association of depressive mood and irritability during childhood with later suicidality. Objective:To investigate the association of childhood irritability and depressive/anxious mood profiles with adolescent suicidality. Design, Setting, and Participants:This population-based cohort study included 1430 participants in the Québec Longitudinal Study of Child Development. Participants underwent assessment yearly or bi-yearly (5 months to 17 years). Data were collected from March 16, 1998, through July 17, 2015. Exposures:Profiles defined by the joint developmental trajectories of irritability and depressive/anxious mood at 6 to 12 years of age. Main Outcomes and Measures:Self-reported past-year suicidality (ie, serious suicidal ideation or suicide attempt) at 13, 15, and 17 years of age. Irritability and depressive/anxious mood were assessed using teacher report 5 times from 6 to 12 years of age. Results:The study included 1430 participants (676 boys [47.3%] and 754 girls [52.7%]) followed up to 17 years of age. Group-based multitrajectory modeling identified the following profiles: combined no irritability and low depressive/anxious mood with low irritability and low depressive/anxious mood (831 [58.1%]; reference group), moderate irritability and low depressive/anxious mood (353 [24.7%]), high depressive/anxious mood only (94 [6.6%]), and high irritability and depressive/anxious mood (152 [10.6%]). Children with high irritability and high depressive/anxious mood reported higher rates of suicidality (25 of 152 [16.4%]) compared with the group with the lowest symptom levels (91 of 831 [11.0%]). In logistic regression analyses, the high irritability and depressive/anxious mood profile (odds ratio [OR], 2.22; 95% CI, 1.32-3.74; number needed to be exposed [NNE], 18) was associated with suicidality. To a lesser extent, the moderate irritability and low depressive/anxious mood profile was also associated with suicidality (OR, 1.51; 95% CI, 1.02-2.25; NNE = 48). The high depressive/anxious mood only profile was not associated with later suicidality (OR, 0.96; 95% CI, 0.47-1.95; NNE = -320). The high irritability and depressive/anxious mood profile was associated with a higher suicidal risk compared with the depressive/anxious mood only profile (OR, 2.28; 95% CI, 1.02-5.15). Girls with the high irritability and high depressive/anxious mood profile had higher risk for suicidality (OR, 3.07; 95% CI, 1.54-6.12; NNE = 5). Conclusions and Relevance:Children with high irritability and depressive/anxious mood and, to a lesser extent, with moderate irritability only had a higher suicidal risk during adolescence compared with children with low symptom levels. Early manifestation of chronic irritability during childhood, especially when combined with depressive/anxious mood, may be associated with an elevated risk for adolescent suicidality. The putatively causal role of irritability should be investigated.
Genome-wide association analyses identify 44 risk variants and refine the genetic architecture of major depression.
Wray Naomi R,Ripke Stephan,Mattheisen Manuel,Trzaskowski Maciej,Byrne Enda M,Abdellaoui Abdel,Adams Mark J,Agerbo Esben,Air Tracy M,Andlauer Till M F,Bacanu Silviu-Alin,Bækvad-Hansen Marie,Beekman Aartjan F T,Bigdeli Tim B,Binder Elisabeth B,Blackwood Douglas R H,Bryois Julien,Buttenschøn Henriette N,Bybjerg-Grauholm Jonas,Cai Na,Castelao Enrique,Christensen Jane Hvarregaard,Clarke Toni-Kim,Coleman Jonathan I R,Colodro-Conde Lucía,Couvy-Duchesne Baptiste,Craddock Nick,Crawford Gregory E,Crowley Cheynna A,Dashti Hassan S,Davies Gail,Deary Ian J,Degenhardt Franziska,Derks Eske M,Direk Nese,Dolan Conor V,Dunn Erin C,Eley Thalia C,Eriksson Nicholas,Escott-Price Valentina,Kiadeh Farnush Hassan Farhadi,Finucane Hilary K,Forstner Andreas J,Frank Josef,Gaspar Héléna A,Gill Michael,Giusti-Rodríguez Paola,Goes Fernando S,Gordon Scott D,Grove Jakob,Hall Lynsey S,Hannon Eilis,Hansen Christine Søholm,Hansen Thomas F,Herms Stefan,Hickie Ian B,Hoffmann Per,Homuth Georg,Horn Carsten,Hottenga Jouke-Jan,Hougaard David M,Hu Ming,Hyde Craig L,Ising Marcus,Jansen Rick,Jin Fulai,Jorgenson Eric,Knowles James A,Kohane Isaac S,Kraft Julia,Kretzschmar Warren W,Krogh Jesper,Kutalik Zoltán,Lane Jacqueline M,Li Yihan,Li Yun,Lind Penelope A,Liu Xiaoxiao,Lu Leina,MacIntyre Donald J,MacKinnon Dean F,Maier Robert M,Maier Wolfgang,Marchini Jonathan,Mbarek Hamdi,McGrath Patrick,McGuffin Peter,Medland Sarah E,Mehta Divya,Middeldorp Christel M,Mihailov Evelin,Milaneschi Yuri,Milani Lili,Mill Jonathan,Mondimore Francis M,Montgomery Grant W,Mostafavi Sara,Mullins Niamh,Nauck Matthias,Ng Bernard,Nivard Michel G,Nyholt Dale R,O'Reilly Paul F,Oskarsson Hogni,Owen Michael J,Painter Jodie N,Pedersen Carsten Bøcker,Pedersen Marianne Giørtz,Peterson Roseann E,Pettersson Erik,Peyrot Wouter J,Pistis Giorgio,Posthuma Danielle,Purcell Shaun M,Quiroz Jorge A,Qvist Per,Rice John P,Riley Brien P,Rivera Margarita,Saeed Mirza Saira,Saxena Richa,Schoevers Robert,Schulte Eva C,Shen Ling,Shi Jianxin,Shyn Stanley I,Sigurdsson Engilbert,Sinnamon Grant B C,Smit Johannes H,Smith Daniel J,Stefansson Hreinn,Steinberg Stacy,Stockmeier Craig A,Streit Fabian,Strohmaier Jana,Tansey Katherine E,Teismann Henning,Teumer Alexander,Thompson Wesley,Thomson Pippa A,Thorgeirsson Thorgeir E,Tian Chao,Traylor Matthew,Treutlein Jens,Trubetskoy Vassily,Uitterlinden André G,Umbricht Daniel,Van der Auwera Sandra,van Hemert Albert M,Viktorin Alexander,Visscher Peter M,Wang Yunpeng,Webb Bradley T,Weinsheimer Shantel Marie,Wellmann Jürgen,Willemsen Gonneke,Witt Stephanie H,Wu Yang,Xi Hualin S,Yang Jian,Zhang Futao, , ,Arolt Volker,Baune Bernhard T,Berger Klaus,Boomsma Dorret I,Cichon Sven,Dannlowski Udo,de Geus E C J,DePaulo J Raymond,Domenici Enrico,Domschke Katharina,Esko Tõnu,Grabe Hans J,Hamilton Steven P,Hayward Caroline,Heath Andrew C,Hinds David A,Kendler Kenneth S,Kloiber Stefan,Lewis Glyn,Li Qingqin S,Lucae Susanne,Madden Pamela F A,Magnusson Patrik K,Martin Nicholas G,McIntosh Andrew M,Metspalu Andres,Mors Ole,Mortensen Preben Bo,Müller-Myhsok Bertram,Nordentoft Merete,Nöthen Markus M,O'Donovan Michael C,Paciga Sara A,Pedersen Nancy L,Penninx Brenda W J H,Perlis Roy H,Porteous David J,Potash James B,Preisig Martin,Rietschel Marcella,Schaefer Catherine,Schulze Thomas G,Smoller Jordan W,Stefansson Kari,Tiemeier Henning,Uher Rudolf,Völzke Henry,Weissman Myrna M,Werge Thomas,Winslow Ashley R,Lewis Cathryn M,Levinson Douglas F,Breen Gerome,Børglum Anders D,Sullivan Patrick F,
Major depressive disorder (MDD) is a common illness accompanied by considerable morbidity, mortality, costs, and heightened risk of suicide. We conducted a genome-wide association meta-analysis based in 135,458 cases and 344,901 controls and identified 44 independent and significant loci. The genetic findings were associated with clinical features of major depression and implicated brain regions exhibiting anatomical differences in cases. Targets of antidepressant medications and genes involved in gene splicing were enriched for smaller association signal. We found important relationships of genetic risk for major depression with educational attainment, body mass, and schizophrenia: lower educational attainment and higher body mass were putatively causal, whereas major depression and schizophrenia reflected a partly shared biological etiology. All humans carry lesser or greater numbers of genetic risk factors for major depression. These findings help refine the basis of major depression and imply that a continuous measure of risk underlies the clinical phenotype.
Association of Increased Chronicity of Depression With HIV Appointment Attendance, Treatment Failure, and Mortality Among HIV-Infected Adults in the United States.
Pence Brian W,Mills Jon C,Bengtson Angela M,Gaynes Bradley N,Breger Tiffany L,Cook Robert L,Moore Richard D,Grelotti David J,O'Cleirigh Conall,Mugavero Michael J
Importance:Depression commonly affects adults with HIV and complicates the management of HIV. Depression among individuals with HIV tends to be chronic and cyclical, but the association of this chronicity with HIV outcomes (and the related potential for screening and intervention to shorten depressive episodes) has received little attention. Objective:To examine the association between increased chronicity of depression and multiple HIV care continuum indicators (HIV appointment attendance, treatment failure, and mortality). Design, Setting, and Participants:The study comprised an observational clinical cohort of 5927 patients with 2 or more assessments of depressive severity who were receiving HIV primary care at 6 geographically dispersed US academic medical centers from September 22, 2005, to August 6, 2015. Main Outcomes and Measures:Missing a scheduled HIV primary care visit, detectable HIV RNA viral load (≥75 copies/mL), and all-cause mortality. Consecutive depressive severity measures were converted into a time-updated measure: percentage of days with depression (PDD), following established methods for determining depression-free days. Results:During 10 767 person-years of follow-up, the 5927 participants (5000 men, 926 women, and 1 intersex individual; median age, 44 years [range, 35-50 years]) had a median PDD of 14% (interquartile range, 0%-48%). During follow-up, 10 361 of 55 040 scheduled visits (18.8%) were missed, 6191 of 28 455 viral loads (21.8%) were detectable, and the mortality rate was 1.5 deaths per 100 person-years. Percentage of days with depression showed a dose-response relationship with each outcome. Each 25% increase in PDD led to an 8% increase in the risk of missing a scheduled appointment (risk ratio, 1.08; 95% CI, 1.05-1.11), a 5% increase in the risk of a detectable viral load (risk ratio, 1.05; 95% CI, 1.01-1.09), and a 19% increase in the mortality hazard (hazard ratio, 1.19; 95% CI, 1.05-1.36). These estimates imply that, compared with patients who spent no follow-up time with depression (PDD, 0%), those who spent the entire follow-up time with depression (PDD, 100%) faced a 37% increased risk of missing appointments (risk ratio, 1.37; 95% CI, 1.22-1.53), a 23% increased risk of a detectable viral load (risk ratio, 1.23; 95% CI, 1.06-1.43), and a doubled mortality rate (hazard ratio, 2.02; 95% CI, 1.20-3.42). Conclusions and Relevance:Greater chronicity of depression increased the likelihood of failure at multiple points along the HIV care continuum. Even modest increases in the proportion of time spent with depression led to clinically meaningful increases in negative outcomes. Clinic-level trials of protocols to promptly identify and appropriately treat depression among adults living with HIV should be conducted to understand the effect of such protocols on shortening the course and preventing the recurrence of depressive illness and improving clinical outcomes.
Association of Depression With Risk of Incident Systemic Lupus Erythematosus in Women Assessed Across 2 Decades.
Importance:It has long been hypothesized that depression may increase the risk of developing autoimmune disease; however, rigorous empirical evidence is sparse. Objective:To evaluate whether an association exists between depression and risk of incident systemic lupus erythematosus (SLE), a paradigmatic, systemic autoimmune disease. Design, Setting, and Participants:This 20-year prospective, longitudinal cohort study evaluated data collected from 2 cohorts of women participating in the Nurses' Health Study (1996-2012) and the Nurses' Health Study II (1993-2013). Data analyses were conducted from August 2017 to May 2018. Main Outcomes and Measures:Incident SLE with 4 or more American College of Rheumatology criteria was ascertained by self-report and confirmed by medical record review. Depression was assessed repeatedly throughout follow-up according to whether women reported having received a clinician's diagnosis of depression, regular antidepressant use, or a score of less than 60 on the 5-item Mental Health Inventory (MHI-5). Whether longitudinally assessed health risk factors (eg, cigarette smoking, body mass index, oral contraceptive use, menopause or postmenopausal hormone use, alcohol use, exercise, or diet) accounted for increased SLE risk among women with vs without depression was examined. Cox proportional hazards regression models were used to estimate risk of SLE. In addition, the association of depression lagged by 4 years, and depression status at baseline with incident SLE throughout follow-up was assessed. Results:Data from 194 483 women (28-93 years of age; 93% white) were included. During 20 years of follow-up, 145 cases of SLE occurred. Compared with women with no depression, women with a history of depression had a subsequent increased risk of SLE (HR, 2.67; 95% CI, 1.91-3.75; P < .001). Adjustment for body mass index, cigarette smoking, and oral contraception and postmenopausal hormone use slightly attenuated associations (adjusted HR, 2.45; 95% CI, 1.74-3.45; P < .001). The SLE risk was elevated with each of the 3 following depression indicators modeled separately: clinician's diagnosis of depression (HR, 2.19; 95% CI, 1.29-3.71), antidepressant use (HR, 2.80; 95% CI, 1.94-4.05), and MHI-5 scores indicating depressed mood (HR, 1.70; 95% CI, 1.18-2.44). Associations remained strong when depression status was lagged by 4 years with respect to the outcome (HR, 1.99; 95% CI, 1.32-3.00) and when depression status at baseline was used as the exposure (HR, 2.28; 95% CI, 1.54-3.37). Conclusions and Relevance:This study contributes to increasing evidence that depression may be associated with increased risk of SLE and suggests that the association is not fully explained by measured health factors or behaviors.
Risk of Psychosis in Recurrent Episodes of Psychotic and Nonpsychotic Major Depressive Disorder: A Systematic Review and Meta-Analysis.
Nelson J Craig,Bickford David,Delucchi Kevin,Fiedorowicz Jess G,Coryell William H
The American journal of psychiatry
OBJECTIVE:The authors conducted a systematic review and meta-analysis to determine whether the risk of psychosis is higher in past or future episodes in patients with major depression with psychotic features than in patients with nonpsychotic depression. METHOD:PubMed, Embase, and PsycINFO were searched, and studies were selected that 1) identified patients with unipolar major depression, 2) made diagnoses of psychosis based on the presence of delusions or hallucinations, 3) characterized past or subsequent episodes as psychotic or nonpsychotic, and 4) were published in English. Two meta-analyses were then conducted using data from patients having index depressive episodes with or without psychosis at study entry to determine the risk of any prior or subsequent psychotic episode and the risk of psychosis in all episodes. RESULTS:Twelve studies met the inclusion criteria, and altogether they included 546 psychotic and 1,583 nonpsychotic patients with unipolar depression. In seven of the studies, the risk ratio for a prior or subsequent psychotic episode in patients whose index depressive episode was psychotic compared with those whose index episode was nonpsychotic was 9.98 (95% CI=4.75, 20.94). In eight studies, the risk ratio for psychosis among all episodes of depression in the subgroups with psychotic and nonpsychotic index episodes was 7.24 (95% CI=5.03, 10.43). Differences in risk of psychosis between these subgroups remained robust when potential sources of heterogeneity were explored. CONCLUSIONS:The findings support the hypothesis that psychotic depression runs true to form, and they support the distinction between psychotic and nonpsychotic depression. Because patients with psychotic depression are at high risk for psychosis in future episodes, determination of effective preventive treatments is imperative.
Risk Factors for Depression: An Autobiographical Review.
Annual review of clinical psychology
I have been given a priceless opportunity to reflect on my career in the remarkably productive field of risk factors for depression. Psychological research on depression exploded in the early years of my work. I try to give an account of the choices and challenges, and reflect on the influences, some calculated and some serendipitous, that determined the paths I have followed. I focus mostly on the robust depression risk factors that have influenced my research, including dysfunctional cognitions, stressful life events and circumstances, parental depression, interpersonal dysfunction, and being female, and I cover some of what I did but also the influential work of others. This is a selective review of depression research in the past 40 or so years, noting some of the big developments that set the stage for the remarkable activity that continues today. In the conclusion, there is a brief statement of aspirations for future developments in our field.
FoxO1, A2M, and TGF-β1: three novel genes predicting depression in gene X environment interactions are identified using cross-species and cross-tissues transcriptomic and miRNomic analyses.
Cattaneo Annamaria,Cattane Nadia,Malpighi Chiara,Czamara Darina,Suarez Anna,Mariani Nicole,Kajantie Eero,Luoni Alessia,Eriksson Johan G,Lahti Jari,Mondelli Valeria,Dazzan Paola,Räikkönen Katri,Binder Elisabeth B,Riva Marco A,Pariante Carmine M
To date, gene-environment (GxE) interaction studies in depression have been limited to hypothesis-based candidate genes, since genome-wide (GWAS)-based GxE interaction studies would require enormous datasets with genetics, environmental, and clinical variables. We used a novel, cross-species and cross-tissues "omics" approach to identify genes predicting depression in response to stress in GxE interactions. We integrated the transcriptome and miRNome profiles from the hippocampus of adult rats exposed to prenatal stress (PNS) with transcriptome data obtained from blood mRNA of adult humans exposed to early life trauma, using a stringent statistical analyses pathway. Network analysis of the integrated gene lists identified the Forkhead box protein O1 (FoxO1), Alpha-2-Macroglobulin (A2M), and Transforming Growth Factor Beta 1 (TGF-β1) as candidates to be tested for GxE interactions, in two GWAS samples of adults either with a range of childhood traumatic experiences (Grady Study Project, Atlanta, USA) or with separation from parents in childhood only (Helsinki Birth Cohort Study, Finland). After correction for multiple testing, a meta-analysis across both samples confirmed six FoxO1 SNPs showing significant GxE interactions with early life emotional stress in predicting depressive symptoms. Moreover, in vitro experiments in a human hippocampal progenitor cell line confirmed a functional role of FoxO1 in stress responsivity. In secondary analyses, A2M and TGF-β1 showed significant GxE interactions with emotional, physical, and sexual abuse in the Grady Study. We therefore provide a successful 'hypothesis-free' approach for the identification and prioritization of candidate genes for GxE interaction studies that can be investigated in GWAS datasets.
Linking unfolded protein response to inflammation and depression: potential pathologic and therapeutic implications.
Ii Timberlake Matthew,Dwivedi Yogesh
Depression is a devastating mental disorder that affects millions of people worldwide. Inflammation has been shown to be a key factor involved in the underlying pathophysiology of depression and has been shown in a substantial proportion of cases of depression. Changes attributed with morphological deformities and immunomodulation in susceptible regions of the depressed brain raised the possibility of altered cellular homeostasis transduced by the intracellular stress response. How emotional stressors can lead to an inflamed brain that directly affects physiology and activity is yet to be fully understood. The unfolded protein response (UPR) has been shown to be active in both models of depression as well as in postmortem brain of depressed individuals. The UPR is the cellular response to stress which results in misfolded proteins. Interestingly, UPR activation is directly linked to both inflammatory cytokine production and Toll-like receptor (TLR) expression. The TLRs are part of the innate immune response which typically reacts to "classic invasions" such as bacteria or viruses as well as trauma. TLRs have also been shown to be upregulated in depression, thus solidifying the connection between inflammation and depression. In this review, we aim to tie the UPR-TLR response and depression, and describe the implications of such an association. We also propose future directions for their role in treatment for depression.
Clinical, cortical thickness and neural activity predictors of future affective lability in youth at risk for bipolar disorder: initial discovery and independent sample replication.
Bertocci Michele A,Hanford Lindsay,Manelis Anna,Iyengar Satish,Youngstrom Eric A,Gill Mary Kay,Monk Kelly,Versace Amelia,Bonar Lisa,Bebko Genna,Ladouceur Cecile D,Perlman Susan B,Diler Rasim,Horwitz Sarah M,Arnold L Eugene,Hafeman Danella,Travis Michael J,Kowatch Robert,Holland Scott K,Fristad Mary A,Findling Robert L,Birmaher Boris,Phillips Mary L
We aimed to identify markers of future affective lability in youth at bipolar disorder risk from the Pittsburgh Bipolar Offspring Study (BIOS) (n = 41, age = 14, SD = 2.30), and validate these predictors in an independent sample from the Longitudinal Assessment of Manic Symptoms study (LAMS) (n = 55, age = 13.7, SD = 1.9). We included factors of mixed/mania, irritability, and anxiety/depression (29 months post MRI scan) in regularized regression models. Clinical and demographic variables, along with neural activity during reward and emotion processing and gray matter structure in all cortical regions at baseline, were used to predict future affective lability factor scores, using regularized regression. Future affective lability factor scores were predicted in both samples by unique combinations of baseline neural structure, function, and clinical characteristics. Lower bilateral parietal cortical thickness, greater left ventrolateral prefrontal cortex thickness, lower right transverse temporal cortex thickness, greater self-reported depression, mania severity, and age at scan predicted greater future mixed/mania factor score. Lower bilateral parietal cortical thickness, greater right entorhinal cortical thickness, greater right fusiform gyral activity during emotional face processing, diagnosis of major depressive disorder, and greater self-reported depression severity predicted greater irritability factor score. Greater self-reported depression severity predicted greater anxiety/depression factor score. Elucidating unique clinical and neural predictors of future-specific affective lability factors is a step toward identifying objective markers of bipolar disorder risk, to provide neural targets to better guide and monitor early interventions in bipolar disorder at-risk youth.
Associations between age and the course of major depressive disorder: a 2-year longitudinal cohort study.
Schaakxs Roxanne,Comijs Hannie C,Lamers Femke,Kok Rob M,Beekman Aartjan T F,Penninx Brenda W J H
The lancet. Psychiatry
BACKGROUND:Although there is some evidence that older people might have a poorer course of major depressive disorder (MDD) than younger or middle-aged people, and that age-related course differences might affect the optimisation of MDD treatment, large-scale studies with a broad age range, including consistent course assessments, are needed to properly address this issue. Therefore, we aimed to longitudinally examine whether older age was associated with a poorer naturalistic course trajectory of MDD than that of younger ages and to establish which prognostic-clinical, social, and health-factors could explain this potentially poorer course. METHODS:For this longitudinal cohort study, we used baseline and 2-year follow-up data from the Netherlands Study of Depression and Anxiety (NESDA) and the Netherlands Study of Depression in Older Persons (NESDO) cohorts. People aged between 18 and 88 years, with an MDD diagnosis at baseline, and a valid clinical assessment at 2-year follow-up were included. The primary outcome was the 2-year course of MDD, which was assessed by use of four indicators: having a depression diagnosis (MDD or dysthymia) after 2 years, having a chronic symptom course (depressive symptoms present during 80% or more of the 2-year follow-up period), time to remission, and depression severity change. We used multivariate analyses to examine associations between continuous age and these MDD course indicators. We also examined whether prognostic clinical (eg, comorbid anxiety), social (loneliness and social support), and health (body-mass index, pain, and chronic diseases) factors contributed to the differences in the course of MDD between age groups. FINDINGS:Between 2004-2012, baseline and 2-year follow-up data were obtained for 1042 participants from the NESDA and NESDO cohorts, of whom 690 (66%) were women. Older age was significantly associated with a worse 2-year MDD course for all four indicators (MDD diagnosis: odds ratio [OR] 1·08, 95% CI 1·00-1·17; chronic symptom course: OR 1·24, 1·13-1·35; time to remission: hazard ratio [HR] 0·91, 0·87-0·96; and depression severity change: regression coefficient 1·06, p<0·0001; all per 10-year increase). The course of MDD worsened linearly with age, and people aged 70 years or older had the worst outcomes compared with those of the reference group of people aged 18-29 years (MDD diagnosis: OR 2·02, 95% CI 1·18-3·45; chronic symptom course: OR 3·19, 1·74-5·84; time to remission: HR 0·60, 0·44-0·83; and depression severity change: -12·64 [SD 10·85] in those aged 18-29 years and -5·57 [11·14] in those aged 70 years or older). These results were slightly reduced, but remained mostly significant when adjusting for prognostic clinical, social, and health factors. INTERPRETATION:Older age was found to be a consistent and important risk factor for a poorer MDD course, which could not be explained by a range of well established risk factors. Further investigation of potential underlying mechanisms-including the effect of cognitive impairment, for example-is needed to prevent the negative consequences of a long-term MDD burden in older people. FUNDING:Netherlands Organisation for Health Research and Development, Fonds NutsOhra, Stichting tot Steun VCVGZ, NARSAD The Brain and Behaviour Research Fund, and European Union's 7th Framework Programme.
Prevention of Depression in At-Risk Adolescents: Predictors and Moderators of Acute Effects.
Weersing V Robin,Shamseddeen Wael,Garber Judy,Hollon Steven D,Clarke Gregory N,Beardslee William R,Gladstone Tracy R,Lynch Frances L,Porta Giovanna,Iyengar Satish,Brent David A
Journal of the American Academy of Child and Adolescent Psychiatry
OBJECTIVE:To assess predictors and moderators of a cognitive-behavioral prevention (CBP) program for adolescent offspring of parents with depression. METHOD:This 4-site randomized trial evaluated CBP compared to usual community care (UC) in 310 adolescents with familial (parental depression) and individual (youth history of depression or current subsyndromal symptoms) risk for depression. As previously reported by Garber and colleagues, a significant prevention effect favored CBP through 9 months; however, outcomes of CBP and UC did not significantly differ when parents were depressed at baseline. The current study expanded on these analyses and examined a range of demographic, clinical, and contextual characteristics of families as predictors and moderators and used recursive partitioning to construct a classification tree to organize clinical response subgroups. RESULTS:Depression onset was predicted by lower functioning (hazard ratio [HR] = 0.95, 95% CI = 0.92-0.98) and higher hopelessness (HR = 1.06, 95% CI = 1.01-1.11) in adolescents. The superior effect of CBP was diminished when parents were currently depressed at baseline (HR = 6.38, 95% CI = 2.38-17.1) or had a history of hypomania (HR = 67.5, 95% CI = 10.9-417.1), or when adolescents reported higher depressive symptoms (HR = 1.04, 95% CI = 1.00-1.08), higher anxiety (HR = 1.05, 95% CI = 1.01-1.08), higher hopelessness (HR = 1.10, 95% CI = 1.01-1.20), or lower functioning (HR = 0.94, 95% CI = 0.89-1.00) at baseline. Onset rates varied significantly by clinical response cluster (0%-57%). CONCLUSION:Depression in adolescents can be prevented, but programs may produce superior effects when timed at moments of relative wellness in high-risk families. Future programs may be enhanced by targeting modifiable negative clinical indicators of response. CLINICAL TRIAL REGISTRATION INFORMATION:Prevention of Depression in At-Risk Adolescents; http://clinicaltrials.gov/; NCT00073671.
Risk factors for relapse and recurrence of depression in adults and how they operate: A four-phase systematic review and meta-synthesis.
Buckman J E J,Underwood A,Clarke K,Saunders R,Hollon S D,Fearon P,Pilling S
Clinical psychology review
PURPOSE:To review and synthesise prognostic indices that predict subsequent risk, prescriptive indices that moderate treatment response, and mechanisms that underlie each with respect to relapse and recurrence of depression in adults. RESULTS AND CONCLUSIONS:Childhood maltreatment, post-treatment residual symptoms, and a history of recurrence emerged as strong prognostic indicators of risk and each could be used prescriptively to indicate who benefits most from continued or prophylactic treatment. Targeting prognostic indices or their "down-stream" consequences will be particularly beneficial because each is either a cause or a consequence of the causal mechanisms underlying risk of recurrence. The cognitive and neural mechanisms that underlie the prognostic indices are likely addressed by the effects of treatments that are moderated by the prescriptive factors. For example, psychosocial interventions that target the consequences of childhood maltreatment, extending pharmacotherapy or adapting psychological therapies to deal with residual symptoms, or using cognitive or mindfulness-based therapies for those with prior histories of recurrence. Future research that focuses on understanding causal pathways that link childhood maltreatment, or cognitive diatheses, to dysfunction in the neocortical and limbic pathways that process affective information and facilitate cognitive control, might result in more enduring effects of treatments for depression.
Depression and chronic diseases: Co-occurrence and communality of risk factors.
Lotfaliany Mojtaba,Bowe Steven J,Kowal Paul,Orellana Liliana,Berk Michael,Mohebbi Mohammadreza
Journal of affective disorders
BACKGROUND:The aim of current study is to assess the cross-sectional association of chronic non-communicable diseases (diabetes mellitus, arthritis, asthma, chronic lung disease, angina, and stroke) with both diagnosed and undiagnosed depression in the World Health Organization (WHO) Study on global AGEing and adult health (SAGE) Wave 1, a study of adults in six low- and middle-income countries. METHODS:A total of 41,810 participants, aged ≥ 18 years, were included. Depression status was assessed by standard methods derived from the World Mental Health Survey (WHH-CIDI). Undiagnosed depression was defined as a depressed person who did not report history of diagnosis/treatment for depression. Associations between depression/undiagnosed depression and chronic diseases, adjusting for country of residence, demographics and chronic diseases risk factors were assessed. RESULTS:Depression was detected in 2508 (6.0%) cases, from whom 2098 (87%) were undiagnosed. Diabetes (Odds ratio:1.47[95%CI:1.24,1.75]), arthritis (2.14[1.82,2.52]), asthma (3.36[2.73,4.14]), chronic lung disease (3.74[3.10,4.51]), angina (3.20[2.66,3.85]), and stroke (3.14[2.55,3.86]) were associated with depression (p-values < 0.001). Being older, female, underweight, and having lower education, and lower income were positively associated with depression. The estimated odds ratios were similar for undiagnosed depression. LIMITATIONS:Cross-sectional design of study prevent us to determine whether depression followed exposures in time. About 12% of the participant did not have data for depression status and were excluded from the study. CONCLUSIONS:Most depression cases were undiagnosed. Depression/undiagnosed depression were strongly associated with chronic diseases; stronger than what has been reported in developed countries.
Mapping risk factors for depression across the lifespan: An umbrella review of evidence from meta-analyses and Mendelian randomization studies.
Köhler Cristiano A,Evangelou Evangelos,Stubbs Brendon,Solmi Marco,Veronese Nicola,Belbasis Lazaros,Bortolato Beatrice,Melo Matias C A,Coelho Camila A,Fernandes Brisa S,Olfson Mark,Ioannidis John P A,Carvalho André F
Journal of psychiatric research
The development of depression may involve a complex interplay of environmental and genetic risk factors. PubMed and PsycInfo databases were searched from inception through August 3, 2017, to identify meta-analyses and Mendelian randomization (MR) studies of environmental risk factors associated with depression. For each eligible meta-analysis, we estimated the summary effect size and its 95% confidence interval (CI) by random-effects modeling, the 95% prediction interval, heterogeneity with I, and evidence of small-study effects and excess significance bias. Seventy meta-analytic reviews met the eligibility criteria and provided 134 meta-analyses for associations from 1283 primary studies. While 109 associations were nominally significant (P < 0.05), only 8 met the criteria for convincing evidence and, when limited to prospective studies, convincing evidence was found in 6 (widowhood, physical abuse during childhood, obesity, having 4-5 metabolic risk factors, sexual dysfunction, job strain). In studies in which depression was assessed through a structured diagnostic interview, only associations with widowhood, job strain, and being a Gulf War veteran were supported by convincing evidence. Additionally, 8 MR studies were included and provided no consistent evidence for the causal effects of obesity, smoking, and alcohol consumption. The proportion of variance explained by genetic risk factors was extremely small (0.1-0.4%), which limited the evidence provided by the MR studies. Our findings suggest that despite the large number of putative risk factors investigated in the literature, few associations were supported by robust evidence. The current findings may have clinical and research implications for the early identification of individuals at risk for depression.
A reliable global cognitive decline and cortisol as an associated risk factor for patients with late-life depression in the short term: A 1-year prospective study.
Zhong Xiaomei,Ning Yuping,Gu Yong,Wu Zhangying,Ouyang Cong,Liang Wanyuan,Chen Ben,Peng Qi,Mai Naikeng,Wu Yuejie,Chen Xinru,Huang Xingbing,Pan Suyue
Journal of affective disorders
BACKGROUND:Late-life depression is a risk factor of dementia. It may increase the risk of reliable cognitive decline in the short term, and its associated risk factors remain unclear. Cortisol level may be one of the important predictors. OBJECTIVES:To estimate whether patients with late-life depression are at an increased risk for reliable global cognitive declines in 1 year, and explore associated risk factors predicting cognitive declines. METHODS:This prospective 1-year follow-up study involved 148 participants (67 with late-life depression and 81 normal elderly). Global cognitive function was assessed by the Mini-Mental State Examination (MMSE). The reliable global cognitive decline was defined by the reliable change index (RCI) of the MMSE. Factors related to cognitive function (e.g., age, gender, education, duration of depression and severity of depression) were obtained. Serum cortisol levels were measured at baseline. RESULTS:At the 1-year follow-up assessment, 19 patients with late-life depression (28.4%) showed reliable global cognitive declines, a risk that was 6.4 times (95% CIs = 1.3-31.1, p = 0.021) higher than that of normal elderly. Elevated serum cortisol levels and older age were associated with the risk of cognitive decline that was 1.6- and 1.2-times higher (95% CIs = 1.07-2.5, p = 0.02, and 95% CIs = 1.04-1.4, p = 0.01 respectively). LIMITATIONS:Serum cortisol levels were measured only in the morning. CONCLUSIONS:Late-life depression is associated with a greatly increased risk of reliable cognitive decline in short term. Cortisol dysregulation may contribute to the pathology of cognitive decline.
Investigation of possible risk factors for depression in Alzheimer's disease: A systematic review of the evidence.
Steck Natassa,Cooper Claudia,Orgeta Vasiliki
Journal of affective disorders
BACKGROUND:Depression is common in people with Alzheimer's disease (AD), and is associated with increased risk of institutionalization and mortality. Understanding risk factors for depression in AD is key to its development and treatment. METHODS:We searched the MEDLINE, EMBASE, PsycINFO, and CINAL databases for longitudinal prospective cohort studies that evaluated risk factors for depression in people with AD. Two authors independently selected articles for inclusion and assessed quality of studies using predetermined criteria. RESULTS:In seven studies that met the inclusion criteria, 2029 participants were followed up for a median of 5 years. Gender and educational attainment were not predictors of depression risk. History of a past psychiatric disorder and greater cognitive impairment predicted increased risk of depression in more than one study. In single studies, younger age, having a family history of psychiatric disorder, neuroticism, functional decline, presence of sleep disturbance and aggression, and increased cardiovascular risk predicted depression risk. Not being within 6 months of dementia onset and, counterintuitively having two comorbid disorders were protective factors in one study. LIMITATIONS:A small number of studies exist overall and only a few have examined the same risk factors. Most of the studies have measured depression using scales that are not validated in AD. CONCLUSIONS:These results inform a preliminary model of depression risk in people with AD. Unlike in the general population, men and women and those with higher and lower educational levels of attainment may be equally at risk of depression. Clinicians should be aware of these possible differences in the risk profile for depression in AD populations, to assist detection and enable early treatment. Interventions to delay cognitive and functional decline may reduce depression risk.