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.

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.

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.

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.

Genotyping serotonin transporter polymorphisms 5-HTTLPR and rs25531 in European- and African-American subjects from the National Institute of Mental Health's Collaborative Center for Genomic Studies.

A number of studies have suggested DNA sequence variability in the serotonin transporter gene (SLC6A4) between European-American (EA) and African-American (AA) populations, which could be clinically important, given the central role SLC6A4 has in serotonin transmission. However, these studies have had relatively small samples, used self-reported measures of race, and have only tested the promoter-linked polymorphism 5-HTTLPR. Here we genotype 5-HTTLPR and rs25531, a neighboring functional polymorphism, in 954 AA and 2622EA subjects from a National Institute of Mental Health repository sample. Genotyping was performed using fragment analysis by capillary electrophoresis. AA, as compared with EA, groups had lower frequencies of the S allele (0.25 vs 0.43) and SS genotype (0.06 vs 0.19) at 5-HTTLPR, and higher rates of the G allele at rs25531 (0.21 vs 0.075). A rare xL variant at 5-HTTLPR was also more common among AAs (0.017 vs 0.008). When the polymorphisms were redefined into a high- and low-transcription haplotypes, the AA group showed significantly fewer low-transcription variants (χ(2)=4.8, P=0.03). No genotypes were associated with major depression, any anxiety disorder, or neuroticism in either EA or AA populations. This is the largest study to show SLC6A4 genotype differences between EA and AA populations, and the first to include rs25531. Lack of associations with clinical outcomes may reflect untested moderating environmental influences.

Neuronal generators of posterior EEG alpha reflect individual differences in prioritizing personal spirituality.

Prominent posterior EEG alpha is associated with depression and clinical response to antidepressants. Given that religious belief was protective against depression in a longitudinal study of familial risk, we hypothesized that individuals who differed by strength of spiritual beliefs might also differ in EEG alpha. Clinical evaluations and self-reports of the importance of religion or spirituality (R/S) were obtained from 52 participants, and again at 10-y followup when EEG was measured. EEG alpha was quantified using frequency PCA of current source densities (CSD-fPCA). Participants who rated R/S as highly important at initial assessment showed greater alpha compared to those who did not. Those who rated R/S important in both sessions showed greater alpha than those who changed their ratings. EEG differences were particularly well-defined for participants with lifetime depression. Findings extend the view of alpha as a marker for affective processes, suggesting an association with the ontogenesis of spirituality.

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.

The role of fear and anxiety in the familial risk for major depression: a three-generation study.

BACKGROUND: The overlap between anxiety and major depressive disorder (MDD), the increased risk for depression and anxiety in offspring of depressed parents, the sequence of onset with anxiety preceding MDD, and anxiety as a predictor of depression are well established. The specificity of anxiety disorders in these relationships is unclear. This study, using a longitudinal high-risk design, examined whether anxiety disorders associated with the emotions fear and anxiety mediate the association between parental and offspring depression. METHOD: Two hundred and twenty-four second-generation and 155 third-generation descendants at high and low risk for depression because of MDD in the first generation were interviewed over 20 years. Probit and Cox proportional hazard models were fitted with generation 2 (G2) or G3 depression as the outcome and parental MDD as the predictor. In G2 and G3, fear- (phobia or panic) and anxiety-related [overanxious or generalized anxiety disorder (GAD)] disorders were examined as potential mediators of increased risk for offspring depression, due to parental MDD. RESULTS: In G2, fear-related disorders met criteria for mediating the association between parental MDD and offspring MDD whereas anxiety-related disorders did not. These results were consistent, regardless of the analytic methods used. Further investigation of the mediating effect of fear-related disorders by age of onset of offspring MDD suggests that the mediating effect occurs primarily in adolescent onset MDD. The results for G3 appear to follow similar patterns. CONCLUSIONS: These findings support the separation of anxiety disorders into at least two distinct forms, particularly when examining their role in the etiology of depression.

A comparison between screened NIMH and clinically interviewed control samples on neuroticism and extraversion.

The National Institute of Mental Health (NIMH) has supported the collection of DNA samples on over 4000 subjects for use primarily as controls in psychiatric genetic studies. These subjects, though screened online, were not directly interviewed or assessed on family history. We compared this sample to one that was directly interviewed using structured diagnostic assessments on comparable measures of neuroticism and extraversion. The screened sample completed an online self-report based on the Composite International Diagnostic Instrument Short-Form (CIDI-SF). The interviewed sample was assessed by clinically trained personnel using the Schedule for Affective Disorders and Schizophrenia (SADS-LA-IV) and Family History Screen; final diagnoses were made blind to trait scores by a clinician using the best-estimate procedure. Neuroticism and extraversion were assessed on the NEO five-factor inventory (NEO-FFI) and the revised Eysenck Personality Questionnaire short form (EPQ-R). We found that subjects in the NIMH-screened sample who did not report any psychiatric symptoms on the self-report were indistinguishable from interviewed diagnosis free and family history negative controls on neuroticism and extraversion. Subjects in the screened sample who screened positive for anxiety disorders, however, deviated significantly on these measures both from the screened subjects with no self-reported symptoms, as well as from subjects in the interviewed sample diagnosed with comparable disorders. These findings suggest that control groups generated from the NIMH sample should ideally be restricted to subjects free of any self-reported symptoms, regardless of the disorder being addressed, in order to maximize their reflection of diagnosis-free populations.

Rates of lifetime suicide attempt and rates of lifetime major depression in different ethnic groups in the United States.

OBJECTIVE: Rates of major depression and suicide vary across ethnic groups within the US. This also may be true of suicide attempts. METHOD: Data on lifetime suicidal behavior and major depression among Mexican American, Cuban American, and Puerto Rican adults who participated in the Hispanic Health and Nutrition Epidemiologic Survey were pooled with Epidemiological Catchment Area Study data for Blacks, Whites and Hispanics. RESULTS: Rates of major depression ranged from 9.3 (Puerto Ricans) to 3.24% (Cuban Americans). Puerto Ricans and whites had the highest rates of depression. Similarly, suicide attempt rates ranged from 9.1% for Puerto Ricans to 1.9% for Cuban Americans. Puerto Ricans had higher suicide attempt rates compared with other groups. CONCLUSION: This study underscores that there are differences between Hispanic ethnic groups. The impact of the migration process, socioeconomic status, and acculturation may underlie differences in major depression and suicide attempt rates across ethnic groups.

Panic and suicidal ideation in primary care.

The objective of this article is to examine the relationship between panic attacks, panic disorder, and suicidal ideation among primary care patients. A probability sample of 1,007 primary care attenders from a large urban university practice was assessed for current mental disorders and suicidal ideation (past 2 week prevalence) with the PRIME-MD Patient Health Questionnaire. Controlling for major depression, substance use disorders, and sociodemographic variables simultaneously, patients with either panic attacks or panic disorder had significantly increased risks of suicidal ideation. Suicidal ideation was highly associated with major depression and comorbid panic disorder (OR = 15.4) or panic attacks (OR = 7.9). There is need for detection and possible treatment of patients with panic attacks or disorder in primary care, especially among those with co-occurring major depression.

Ethnic and sex differences in suicide rates relative to major depression in the United States.

OBJECTIVE: Suicide rates differ between ethnic groups in the United States. Since suicide is commonly associated with a mood disorder, the authors compared suicide rates relative to depression rates in five ethnic groups in the United States. METHOD: Rates of major depression were generated from the Epidemiologic Catchment Area study and the Hispanic Health and Nutrition Epidemiologic Survey. Sociodemographic effects were determined by examining depression rates for respondents who were separated or divorced, earning low incomes, or not working for pay. The survey data were analyzed with age and sex standardization to generate 1-year prevalence rates of major depression. The depression rates of the different ethnic groups were compared and were examined in relation to suicide rates. RESULTS: The 1-year prevalence rates of major depression were 3.6% for whites, 3.5% for blacks, 2.8% for Mexican Americans, 2.5% for Cuban Americans, and 6.9% for Puerto Ricans. Compared to the rate for whites, the rate of depression was significantly higher in Puerto Ricans and significantly lower in Mexican Americans. Relative to the depression rates, the annual suicide rates were higher for males than for females. Mexican American and Puerto Rican males had lower relative suicide rates than white males. CONCLUSIONS: Identifying reasons for differences in suicide rates relative to depression among ethnic groups and between males and females may suggest interventions to reduce suicide rates. Some possibilities are that depression differs in form or severity or that unidentified factors protect against suicide in different subgroups.

Phenotype definitions: some hidden issues in psychiatry.

Three hidden problems in phenotype definition in psychiatric genetic studies are described. 1. Data on physical conditions in family members are not routinely collected in genetic studies of psychiatric disorders. These data may reveal cosegregation with psychiatric disorders which can be included in genetic analysis when defining the phenotype. Data on physical conditions can be obtained by a combination of medical checklists, medical history, and medical records. 2. Detailed clinical narrative summaries should be prepared on family members even if the narratives are not part of the diagnostic data included in centralized cell repositories for future distribution to qualified genetic investigators. Means for retaining the narratives for future use, while protecting patient confidentiality, should be sought. The narratives include detailed information on the context, severity, and sequence of the symptoms and can provide phenotype descriptions for reconsideration of diagnosis in the future. 3. The selection of early onset psychiatric disorders for genetic studies does not automatically mean that affected children should be included in genetic studies for some psychiatric disorders. Screening for genetic studies among child psychiatric patients and inclusion of children as affected in pedigrees should proceed with caution until more data are available from longitudinal studies on the continuity between childhood and adult psychiatric disorders.

Medically unexplained symptoms in an urban general medicine practice.

The authors investigated the prevalence of multiple medically unexplained symptoms (MMUS) as identified by primary care physicians (PCPs) in a systematic sample of 172 patients. Patients were from a university-affiliated urban primary care practice serving a low-income population. Patients with a history of MMUS were older (mean: 57.2 vs. 53.0 years), more likely to be female (90.5% vs. 72.3%), and less likely to be married or living with a partner (14.4% vs. 36.2%) than those without MMUS. Patients with MMUS had over twice the rate of any current psychiatric disorder, almost two-and-a-half times the rate of any current anxiety disorder, and greater functional impairment. These data suggest that patients with MMUS are as common in urban primary care clinics as in more affluent clinics and reinforce the need for PCPs to screen these patients for common and treatable psychiatric conditions.

The association between childhood depression and adulthood body mass index.

OBJECTIVE: Stress in childhood relates to both childhood depression and elevated adult body mass index (BMI), a measure of relative overweight. However, there are limited data on the association between major depression in childhood and BMI in adulthood. The current study examines this association. METHOD: Children 6 to 17 years old with major depression (n = 90) or no psychiatric disorder (n = 87) were identified at Columbia Presbyterian Medical Center and followed up 10 to 15 years later. Psychiatric status at intake and follow-up was assessed via standardized psychiatric interviews. BMI during adulthood was recorded so that the association between depression and BMI could be considered over time. RESULTS: Participants with childhood major depression had a BMI of 26.1 +/- 5.2 as adults, compared with a BMI of 24.2 +/- 4.1 in healthy comparisons (t(175) = 2.7). This association could not be explained by a number of potentially confounding factors, including age, gender, cigarette or alcohol use, social class, and pregnancy or medication history. Although poverty during adulthood also predicted adult BMI, both the association between poverty and adult BMI (t(152) = 2.9), as well as between childhood depression and adult BMI (t(152) = 2.2) were significant in a multivariate model. Finally, duration of depression between childhood and adulthood also emerged as a predictor of adult BMI. CONCLUSIONS: Depression during childhood is positively associated with BMI during adulthood. This association cannot be explained by various potential confounding variables and may develop over time as children pass into their adult years.body mass index, depression, children, adolescents.

Premorbid polysomnographic signs in depressed adolescents: a reanalysis of EEG sleep after longitudinal follow-up in adulthood.

BACKGROUND: This is a report of a clinical follow-up study (10-15 years later as young adults) of adolescent major depressives and normal control subjects. Polysomnographic data were obtained during the original study period when the subjects were adolescent (time 1). With clinical follow-up (time 2) assessments in hand, our objective was to ascertain whether there were any premorbid polysomnographic signs associated with depression during adolescence. METHODS: Based upon initial (during adolescence) and follow-up clinical assessments (as adults), new subject groupings were generated: depression-free normal subjects and original normal subjects who experienced a depressive episode during the follow-up period (latent depressives). Suicidality and recurrence of depression were also examined. Multivariate analysis of covariance was used to analyze group differences in sleep measures and logistic regression for predicting three outcomes: lifetime depression, lifetime suicidality, and recurrence. RESULTS: Comparison of the depression-free normal subjects, the latent depressives, and the original major depressives revealed significant differences for sleep latency and sleep period time. Comparing all lifetime depressives (original major depressives and the latent depressives) to depression-free normal subjects revealed significantly more stages 3 and 4 combined (ST34) sleep and greater sleep period times among the depressives. An analysis involving the presence or absence of suicidality revealed no overall significant differences between the groups. Comparison of the lifetime depressives grouped by nonrecurrent and recurrent depressive course to the depression-free normal subjects revealed significant difference for sleep period time. Using logistic regression, we found that a longer sleep latency and sleep period time significantly predicted lifetime depression. Gender, ST34 sleep, and an interaction term for ST34 sleep and REM latency significantly predicted lifetime suicidality. CONCLUSIONS: There was evidence of premorbid sleep abnormalities during adolescence. A general pattern of sleep disruption around sleep onset and during the first 100 min of the sleep period and overall sleep was evident among the major and lifetime depressives, involving sleep latency (initial insomnia), sleep period time (hypersomnia), REM latency, and slow-wave sleep. This adds to the body of literature that highlights the importance of the first 100 min of the sleep period in depression.