Polygenic interactions with environmental adversity in the aetiology of major depressive disorder.

BACKGROUND: Major depressive disorder (MDD) is a common and disabling condition with well-established heritability and environmental risk factors. Gene-environment interaction studies in MDD have typically investigated candidate genes, though the disorder is known to be highly polygenic. This study aims to test for interaction between polygenic risk and stressful life events (SLEs) or childhood trauma (CT) in the aetiology of MDD. METHOD: The RADIANT UK sample consists of 1605 MDD cases and 1064 controls with SLE data, and a subset of 240 cases and 272 controls with CT data. Polygenic risk scores (PRS) were constructed using results from a mega-analysis on MDD by the Psychiatric Genomics Consortium. PRS and environmental factors were tested for association with case/control status and for interaction between them. RESULTS: PRS significantly predicted depression, explaining 1.1% of variance in phenotype (p = 1.9 × 10(-6)). SLEs and CT were also associated with MDD status (p = 2.19 × 10(-4) and p = 5.12 × 10(-20), respectively). No interactions were found between PRS and SLEs. Significant PRSxCT interactions were found (p = 0.002), but showed an inverse association with MDD status, as cases who experienced more severe CT tended to have a lower PRS than other cases or controls. This relationship between PRS and CT was not observed in independent replication samples. CONCLUSIONS: CT is a strong risk factor for MDD but may have greater effect in individuals with lower genetic liability for the disorder. Including environmental risk along with genetics is important in studying the aetiology of MDD and PRS provide a useful approach to investigating gene-environment interactions in complex traits.

Type I interferon signaling genes in recurrent major depression: increased expression detected by whole-blood RNA sequencing.

A study of genome-wide gene expression in major depressive disorder (MDD) was undertaken in a large population-based sample to determine whether altered expression levels of genes and pathways could provide insights into biological mechanisms that are relevant to this disorder. Gene expression studies have the potential to detect changes that may be because of differences in common or rare genomic sequence variation, environmental factors or their interaction. We recruited a European ancestry sample of 463 individuals with recurrent MDD and 459 controls, obtained self-report and semi-structured interview data about psychiatric and medical history and other environmental variables, sequenced RNA from whole blood and genotyped a genome-wide panel of common single-nucleotide polymorphisms. We used analytical methods to identify MDD-related genes and pathways using all of these sources of information. In analyses of association between MDD and expression levels of 13 857 single autosomal genes, accounting for multiple technical, physiological and environmental covariates, a significant excess of low P-values was observed, but there was no significant single-gene association after genome-wide correction. Pathway-based analyses of expression data detected significant association of MDD with increased expression of genes in the interferon α/ß signaling pathway. This finding could not be explained by potentially confounding diseases and medications (including antidepressants) or by computationally estimated proportions of white blood cell types. Although cause-effect relationships cannot be determined from these data, the results support the hypothesis that altered immune signaling has a role in the pathogenesis, manifestation, and/or the persistence and progression of MDD.

The effects on children of depressed mothers' remission and relapse over 9 months.

BACKGROUND: The high rate of depression among children of depressed mothers is well known. Suggestions that improvement in maternal acute depression has a positive effect on the child have emerged. However, data on the mechanisms of change have been sparse. The aim was to understand how remission and relapse in the mother might explain the changes in the child's outcome. METHOD: Participants were 76 depressed mothers who entered into a medication clinical trial for depression and 135 of their eligible offspring ages 7-17 years. The mothers and children were assessed at baseline and periodically over 9 months by independent teams to understand the relationship between changes in children's symptoms and functioning and maternal remission or relapse. The main outcome measures were, for mothers, the Hamilton Depression Rating Scale (HAMD), the Social Adjustment Scale (SAS) and the Parental Bonding Instrument (PBI) and, for children, the Children's Depression Inventory (CDI), the Columbia Impairment Scale (CIS), the Multidimensional Anxiety Scale for Children (MASC) and the Children's Global Assessment Scale (CGAS). RESULTS: Maternal remission was associated with a decrease in the child's depressive symptoms. The mother's subsequent relapse was associated with an increase in the child's symptoms over 9 months. The effect of maternal remission on the child's improvement was partially explained by an improvement in the mother's parenting, particularly the change in the mother's ability to listen and talk to her child, but also reflected in her improvement in parental bonding. These findings could not be explained by the child's treatment. CONCLUSIONS: A depressed mother's remission is associated with her improvement in parenting and a decrease in her child's symptoms. Her relapse is associated with an increase in her child's symptoms.

Depression and cognition are associated with lipid dysregulation in both a multigenerational study of depression and the National Health and Nutrition Examination Survey.

Chronic dysregulation of peripheral lipids has been found to be associated with depression and cognition, but their interaction has not been investigated. Growing evidence has highlighted the association between peripheral lipoprotein levels with depression and cognition with inconsistent results. We assessed the association between peripheral lipids, depression, and cognition while evaluating their potential interactions using robust clinically relevant predictors such as lipoprotein levels and chronic medical disorders that dysregulate lipoproteins. We report an association between peripheral lipids, depression, and cognition, suggesting a common underlying biological mechanism driven by lipid dysregulation in two independent studies. Analysis of a longitudinal study of a cohort at high or low familial risk for major depressive disorder (MDD) (n = 526) found metabolic diseases, including diabetes, hypertension, and other cardiovascular diseases, were associated with MDD and cognitive outcomes. Investigating a cross-sectional population survey of adults in the National Health and Nutrition Examination Survey 2011-2014 (NHANES) (n = 2377), depression was found to be associated with high density lipoprotein (HDL) and cognitive assessments. In the familial risk study, medical conditions were found to be associated with chronic lipid dysregulation and were significantly associated with MDD using the structural equation model. A positive association between chronic lipid dysregulation and cognitive scores was found in an exploratory analysis of the familial risk study. In a complementary study, analysis of NHANES revealed a positive association of HDL levels with cognition. Further analysis of the NHANES cohort indicated that depression status mediated the interaction between HDL levels and cognitive tests. Importantly, the protective effect of HDL on cognition was absent in those with depressive symptoms, which may ultimately result in worse outcomes leading to cognitive decline. These findings highlight the potential for the early predictive value of medical conditions with chronic lipid dyshomeostasis for the risk of depression and cognitive decline.

Religiosity and resilience in persons at high risk for major depression.

BACKGROUND: Few studies have examined religiosity as a protective factor using a longitudinal design to predict resilience in persons at high risk for major depressive disorder (MDD). METHOD: High-risk offspring selected for having a depressed parent and control offspring of non-depressed parents were evaluated for psychiatric disorders in childhood/adolescence and at 10-year and 20-year follow-ups. Religious/spiritual importance, services attendance and negative life events (NLEs) were assessed at the 10-year follow-up. Models tested differences in relationships between religiosity/spirituality and subsequent disorders among offspring based on parent depression status, history of prior MDD and level of NLE exposure. Resilience was defined as lower odds for disorders with greater religiosity/spirituality in higher-risk versus lower-risk offspring. RESULTS: Increased attendance was associated with significantly reduced odds for mood disorder (by 43%) and any psychiatric disorder (by 53%) in all offspring; however, odds were significantly lower in offspring of non-depressed parents than in offspring of depressed parents. In analyses confined to offspring of depressed parents, those with high and those with average/low NLE exposure were compared: increased attendance was associated with significantly reduced odds for MDD, mood disorder and any psychiatric disorder (by 76, 69 and 64% respectively) and increased importance was associated with significantly reduced odds for mood disorder (by 74%) only in offspring of depressed parents with high NLE exposure. Moreover, those associations differed significantly between offspring of depressed parents with high NLE exposure and offspring of depressed parents with average/low NLE exposure. CONCLUSIONS: Greater religiosity may contribute to development of resilience in certain high-risk individuals.

Genome-wide association study of recurrent early-onset major depressive disorder.

A genome-wide association study was carried out in 1020 case subjects with recurrent early-onset major depressive disorder (MDD) (onset before age 31) and 1636 control subjects screened to exclude lifetime MDD. Subjects were genotyped with the Affymetrix 6.0 platform. After extensive quality control procedures, 671 424 autosomal single nucleotide polymorphisms (SNPs) and 25 068 X chromosome SNPs with minor allele frequency greater than 1% were available for analysis. An additional 1 892 186 HapMap II SNPs were analyzed based on imputed genotypic data. Single-SNP logistic regression trend tests were computed, with correction for ancestry-informative principal component scores. No genome-wide significant evidence for association was observed, assuming that nominal P<5 × 10(-8) approximates a 5% genome-wide significance threshold. The strongest evidence for association was observed on chromosome 18q22.1 (rs17077540, P=1.83 × 10(-7)) in a region that has produced some evidence for linkage to bipolar-I or -II disorder in several studies, within an mRNA detected in human brain tissue (BC053410) and approximately 75 kb upstream of DSEL. Comparing these results with those of a meta-analysis of three MDD GWAS data sets reported in a companion article, we note that among the strongest signals observed in the GenRED sample, the meta-analysis provided the greatest support (although not at a genome-wide significant level) for association of MDD to SNPs within SP4, a brain-specific transcription factor. Larger samples will be required to confirm the hypothesis of association between MDD (and particularly the recurrent early-onset subtype) and common SNPs.

Novel loci for major depression identified by genome-wide association study of Sequenced Treatment Alternatives to Relieve Depression and meta-analysis of three studies.

We report a genome-wide association study (GWAS) of major depressive disorder (MDD) in 1221 cases from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study and 1636 screened controls. No genome-wide evidence for association was detected. We also carried out a meta-analysis of three European-ancestry MDD GWAS data sets: STAR*D, Genetics of Recurrent Early-onset Depression and the publicly available Genetic Association Information Network-MDD data set. These data sets, totaling 3957 cases and 3428 controls, were genotyped using four different platforms (Affymetrix 6.0, 5.0 and 500 K, and Perlegen). For each of 2.4 million HapMap II single-nucleotide polymorphisms (SNPs), using genotyped data where available and imputed data otherwise, single-SNP association tests were carried out in each sample with correction for ancestry-informative principal components. The strongest evidence for association in the meta-analysis was observed for intronic SNPs in ATP6V1B2 (P=6.78 x 10⁻7), SP4 (P=7.68 x 10⁻7) and GRM7 (P=1.11 x 10⁻6). Additional exploratory analyses were carried out for a narrower phenotype (recurrent MDD with onset before age 31, N=2191 cases), and separately for males and females. Several of the best findings were supported primarily by evidence from narrow cases or from either males or females. On the basis of previous biological evidence, we consider GRM7 a strong MDD candidate gene. Larger samples will be required to determine whether any common SNPs are significantly associated with MDD.

Panic disorder is associated with the serotonin transporter gene (SLC6A4) but not the promoter region (5-HTTLPR).

Panic disorder (PD) and social anxiety disorder (SAD) are moderately heritable anxiety disorders. We analyzed five genes, derived from pharmacological or translational mouse models, in a new case-control study of PD and SAD in European Americans: (1) the serotonin transporter (SLC6A4), (2) the serotonin receptor 1A, (3) catechol-O-methyltransferase, (4) a regulator of g-protein signaling and (5) the gastrin-releasing peptide receptor. Cases were interviewed using the schedule for affective disorders and schizophrenia and were required to have a probable or definite lifetime diagnosis of PD (N=179), SAD (161) or both (140), with first onset by age 31 and a family history of anxiety. Final diagnoses were determined using the best estimate procedure, blind to genotyping data. Controls were obtained from the National Institute of Mental Health Human Genetics Initiative; only subjects above 25 years of age who screened negative for all psychiatric symptoms were included (N=470). A total of 45 single nucleotide polymorphisms were successfully genotyped over the five selected genes using Applied Biosystems SNPlex protocol. SLC6A4 provided strong and consistent evidence of association with the PD and PD+SAD groups, with the most significant association in both groups being at rs140701 (chi(2)=10.72, P=0.001 with PD and chi(2)=8.59, P=0.003 in the PD+SAD group). This association remained significant after multiple test correction. Those carrying at least one copy of the haplotype A-A-G constructed from rs3794808, rs140701 and rs4583306 have 1.7 times the odds of PD than those without the haplotype (95% confidence interval: 1.2-2.3). The SAD only group did not provide evidence of association, suggesting a PD-driven association. The findings remained after adjustment for age and sex, and there was no evidence that the association was due to population stratification. The promoter region of the gene, 5-HTTLPR, did not provide any evidence of association, regardless of whether analyzed as a triallelic or biallelic locus, nor did any of the other four candidate genes tested. Our findings suggest that the serotonin transporter gene may play a role in PD; however, the findings require replication. Future studies should attend to the entire genetic region rather than the promoter.

Depression in women: implications for health care research.

Epidemiologic data from around the world demonstrate that major depression is approximately twice as common in women than men and that its first onset peaks during the childbearing years. Progress has been made in understanding the epidemiology of depression and in developing effective treatments. Much remains to be learned about the basic pathogenesis of depression and the specific treatment needs of depressed women and their offspring, especially during the reproductive years.

Wrist cutting. Relationship between clinical observations and epidemiological findings.

Reports of select samples have described suicide attempt by wrist cutting as a unique clinical syndrome occurring in young, single, attractive women, associated with specific psychological characteristics. A St. Louis study of a large unselected sample found that persons who cut their wrists were similar to other suicide attempters and were not more apt to be single females who made repeated attempts. These findings are repeated in a New Haven, Conn, study suggesting that reports of persons cutting their wrists should be reconsidered in light of these epidemiologic findings. Institutional differences in patient sampling can account for lack of agreement. While clinical observations are important, additional study through epidemiologic approaches is necessary before conclusions about new syndromes can be made. Current evidence on wrist cutting raises questions about the existence of a separate syndrome.

The psychological treatment of depression. Evidence for the efficacy of psychotherapy alone, in comparison with, and in combination with pharmacotherapy.

Seventeen clinical trials are identified that test the efficacy of various psychological treatments (behavioral, cognitive, group, marital, interpersonal) alone, in comparison with, and in combination with pharmacotherapy in homogeneous samples of depressed outpatients. I describe the results of these studies, gaps in the evidence, and suggestions for future research directions.

The assessment of social adjustment. A review of techniques.

Interest in the community adjustment of psychiatric patients has led to the development of rating techniques for its evaluation. Selection of an appropriate scale for the task should include a review of its item content, anchor points, coverage, method of obtaining information, informant, psychometric properties, precision, cost, scoring, and instructional material. While no scale is without limitations, this report describes 15 currently available scales that meet many of the important criteria for assessing social adjustment and are sufficiently developed to be useful in evaluative research. This review also contains a list of pertinent references to the scales and guide to the literature on behavioral rating scales.

Assessment of social adjustment by patient self-report.

Current emphasis on early case finding, outpatient care, and on longitudinal studies of asymptomatic patients has focused attention on the community adjustment of psychiatric patients. Thus, simple and inexpensive methods such as self-report scales, which allow the routine assessment of patient adjustment, are potentially useful. The derivation and testing of such a method, the Social Adjustment Scale Self-Report, is described. This scale covers the patient's role performance, interpersonal relationships, friction, feelings and satisfaction in work, and social and leisure activities with the extended family, as a spouse, parent, and member of a family unit. Self-report results based on 76 depressed outpatients were comparable to those obtained from relatives as well as by a rater who interviewed the patient directly.

Interpersonal psychotherapy. Current status.

Interpersonal psychotherapy (IPT), a time-limited treatment for major depression, was developed, defined in a manual, and tested in randomized clinical trials by the late Gerald L. Klerman, MD, and collaborators. It has subsequently been modified for different age groups and types of mood and nonmood disorders and for use as a long-term treatment. Having begun as a research intervention, IPT has yet to be well disseminated among clinicians or in residency training programs. The publication of efficacy data, the recent appearance of two practice guidelines that include IPT among treatments for depression, and the interest in defined treatments for managed care have led to increasing requests for information and training.

Sex differences and the epidemiology of depression.

This article reviews the evidence for differing rates of depression between the sexes in the United States and elsewhere during the last 40 years, and then critically analyzes the various explanations offered. These explanations include the possibility that the trends are spurious because of artifacts produced by methods of reporting symptoms, or that they are real because of biological susceptibility (possibly genetic or female endocrine), psychosocial factors such as social discrimination, or female-learned helplessness.

Epidemiology of affective disorders. A reexamination and future directions.

Epidemiologic studies of depression have been difficult to interpret because of differing case definitions and variation in diagnostic procedures between studies. We review data from recent epidemiologic studies in which the new research diagnostic techniques were used. We have divided the data into studies of depressive symptoms, bipolar disorder, and nonbipolar depression. An effort is made to integrate the findings of older studies in light of this new classification. Using this classification, there is less variation in epidemiologic rates (point prevalence, incidence, and lifetime risk) than has been noted in previous reviews. Future directions of research are also discussed.

Affective disorders in a US urban community: the use of research diagnostic criteria in an epidemiological survey.

The current point and lifetime prevalence rates of affective disorders, based on the application of Research Diagnostic Criteria to a US urban community sample, are reported. The affective disorders studied included major and minor depression, mania, hypomania, bipolar I and II, primary and secondary depression, schizo-affective disorder, depressive and cyclothymic personality, and grief reactions. Epidemiologic surveys that include treated and untreated persons to obtain rates of specific psychiatric disorders are needed for scientific purposes and health care planning.

Epidemiology of mental disorders: emerging trends in the United States.

Psychiatric epidemiology in the United States currently is being influenced by developments in genetics, psychopharmacology, neurobiology, and particularly psychopathology after the heavy influences of the social sciences during the post-World War II period. The integration of recent scientific developments in psychiatry, with the methodological precision that characterized the earlier studies of the 50s and 60s promises to provide new knowledge on the epidemiology of mental disorders in the community, which will have important implications both for professional practices in medicine and public health and for public policy in the planning of mental health services, training, and research.

Panic disorder, comorbidity, and suicide attempts.

In a previous report, we demonstrated a strong association between panic disorder and suicide attempts based on data from the Epidemiologic Catchment Area study (a probability sample of more than 18,000 adults living in five US communities). In these analyses, although we controlled statistically for comorbidity of panic disorder with other psychiatric disorders, we did not directly estimate the risk of suicide attempts in persons with uncomplicated panic disorder (ie, without any other Axis I disorders) compared with those with comorbid conditions. Persons with uncomplicated panic disorder represent fewer than a third of persons with panic disorder. However, the lifetime rates of suicide attempts in persons with uncomplicated panic disorder (7%) were consistently higher than for persons with no psychiatric disorder (1%). Similar findings on the rate of suicide attempts in persons with uncomplicated major depression (7.9%) emerged. We conclude that suicide attempts are associated with panic disorder in its uncomplicated or its comorbid form and that the risks are comparable with those of major depression, comorbid and uncomplicated. These epidemiologic findings are discussed within a clinical perspective to explain why these associations may not appear obvious in clinical practice.

The validity of major depression with psychotic features based on a community study.

This article reports on the evidence for the validity of psychotic major depression as a distinct subtype based on cross-sectional and 1-year prospective data from the Epidemiologic Catchment Area study. Consistent with findings from previous clinical studies, only about 14% of major depressions were accompanied by psychotic features. Psychotic as compared with nonpsychotic depression had a more severe course, as reflected in increased risk of relapse, persistence over 1 year, suicide attempts, hospitalization, comorbidity, and financial dependency. These differences could not be explained by differences in demographic characteristics or by symptom severity, as assessed by symptom profile or number of symptoms. The boundary problem with schizophrenia and bipolar affective disorder that is seen in clinical studies was also found in this sample. To our knowledge, this is the first study to examine the validity of psychotic depression in a community sample; the findings are consistent with those from clinical samples. They support the clinical significance of psychotic depression and the continuation of its inclusion as a distinct subtype in DSM-IV.