Confirmatory test of two factors and four subtypes of bipolar disorder based on lifetime psychiatric co-morbidity.

BACKGROUND: The first aim was to use confirmatory factor analysis (CFA) to test a hypothesis that two factors (internalizing and externalizing) account for lifetime co-morbid DSM-IV diagnoses among adults with bipolar I (BPI) disorder. The second aim was to use confirmatory latent class analysis (CLCA) to test the hypothesis that four clinical subtypes are detectible: pure BPI; BPI plus internalizing disorders only; BPI plus externalizing disorders only; and BPI plus internalizing and externalizing disorders. METHOD: A cohort of 699 multiplex BPI families was studied, ascertained and assessed (1998-2003) by the National Institute of Mental Health Genetics Initiative Bipolar Consortium: 1156 with BPI disorder (504 adult probands; 594 first-degree relatives; and 58 more distant relatives) and 563 first-degree relatives without BPI. Best-estimate consensus DSM-IV diagnoses were based on structured interviews, family history and medical records. MPLUS software was used for CFA and CLCA. RESULTS: The two-factor CFA model fit the data very well, and could not be improved by adding or removing paths. The four-class CLCA model fit better than exploratory LCA models or post-hoc-modified CLCA models. The two factors and four classes were associated with distinctive clinical course and severity variables, adjusted for proband gender. Co-morbidity, especially more than one internalizing and/or externalizing disorder, was associated with a more severe and complicated course of illness. The four classes demonstrated significant familial aggregation, adjusted for gender and age of relatives. CONCLUSIONS: The BPI two-factor and four-cluster hypotheses demonstrated substantial confirmatory support. These models may be useful for subtyping BPI disorders, predicting course of illness and refining the phenotype in genetic studies.

Cytomegalovirus Antibody Elevation in Bipolar Disorder: Relation to Elevated Mood States.

The neurobiology of mood states is complicated by exposure to everyday stressors (e.g., psychosocial, ubiquitous environmental infections like CMV), each fluctuating between latency and reactivation. CMV reactivation induces proinflammatory cytokines (e.g., TNF-α) associated with induction of neurotoxic metabolites and the presence of mood states in bipolar disorder (BD). Whether CMV reactivation is associated with bipolar diagnoses (trait) or specific mood states is unclear. We investigated 139 BD type I and 99 healthy controls to determine if concentrations of IgG antibodies to Herpesviridae (e.g., CMV, HSV-1, and HSV-2) were associated with BD-I diagnosis and specific mood states. We found higher CMV antibody concentration in BD-I than in healthy controls (T234 = 3.1, P uncorr = 0.002; P corr = 0.006) but no difference in HSV-1 (P > 0.10) or HSV-2 (P > 0.10). Compared to euthymic BD-I volunteers, CMV IgG was higher in BD-I volunteers with elevated moods (P < 0.03) but not different in depressed moods (P > 0.10). While relationships presented between BD-I diagnosis, mood states, and CMV antibodies are encouraging, they are limited by the study's cross sectional nature. Nevertheless, further testing is warranted to replicate findings and determine whether reactivation of CMV infection exacerbates elevated mood states in BD-I.

Enrichment of cis-regulatory gene expression SNPs and methylation quantitative trait loci among bipolar disorder susceptibility variants.

We conducted a systematic study of top susceptibility variants from a genome-wide association (GWA) study of bipolar disorder to gain insight into the functional consequences of genetic variation influencing disease risk. We report here the results of experiments to explore the effects of these susceptibility variants on DNA methylation and mRNA expression in human cerebellum samples. Among the top susceptibility variants, we identified an enrichment of cis regulatory loci on mRNA expression (eQTLs), and a significant excess of quantitative trait loci for DNA CpG methylation, hereafter referred to as methylation quantitative trait loci (mQTLs). Bipolar disorder susceptibility variants that cis regulate both cerebellar expression and methylation of the same gene are a very small proportion of bipolar disorder susceptibility variants. This finding suggests that mQTLs and eQTLs provide orthogonal ways of functionally annotating genetic variation within the context of studies of pathophysiology in brain. No lymphocyte mQTL enrichment was found, suggesting that mQTL enrichment was specific to the cerebellum, in contrast to eQTLs. Separately, we found that using mQTL information to restrict the number of single-nucleotide polymorphisms studied enhances our ability to detect a significant association. With this restriction a priori informed by the observed functional enrichment, we identified a significant association (rs12618769, P(bonferroni)<0.05) from two other GWA studies (TGen+GAIN; 2191 cases and 1434 controls) of bipolar disorder, which we replicated in an independent GWA study (WTCCC). Collectively, our findings highlight the importance of integrating functional annotation of genetic variants for gene expression and DNA methylation to advance the biological understanding of bipolar disorder.

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.

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.

Singleton deletions throughout the genome increase risk of bipolar disorder.

An overall burden of rare structural genomic variants has not been reported in bipolar disorder (BD), although there have been reports of cases with microduplication and microdeletion. Here, we present a genome-wide copy number variant (CNV) survey of 1001 cases and 1034 controls using the Affymetrix single nucleotide polymorphism (SNP) 6.0 SNP and CNV platform. Singleton deletions (deletions that appear only once in the dataset) more than 100 kb in length are present in 16.2% of BD cases in contrast to 12.3% of controls (permutation P=0.007). This effect was more pronounced for age at onset of mania

Genome-wide association study of bipolar disorder in European American and African American individuals.

To identify bipolar disorder (BD) genetic susceptibility factors, we conducted two genome-wide association (GWA) studies: one involving a sample of individuals of European ancestry (EA; n=1001 cases; n=1033 controls), and one involving a sample of individuals of African ancestry (AA; n=345 cases; n=670 controls). For the EA sample, single-nucleotide polymorphisms (SNPs) with the strongest statistical evidence for association included rs5907577 in an intergenic region at Xq27.1 (P=1.6 x 10(-6)) and rs10193871 in NAP5 at 2q21.2 (P=9.8 x 10(-6)). For the AA sample, SNPs with the strongest statistical evidence for association included rs2111504 in DPY19L3 at 19q13.11 (P=1.5 x 10(-6)) and rs2769605 in NTRK2 at 9q21.33 (P=4.5 x 10(-5)). We also investigated whether we could provide support for three regions previously associated with BD, and we showed that the ANK3 region replicates in our sample, along with some support for C15Orf53; other evidence implicates BD candidate genes such as SLITRK2. We also tested the hypothesis that BD susceptibility variants exhibit genetic background-dependent effects. SNPs with the strongest statistical evidence for genetic background effects included rs11208285 in ROR1 at 1p31.3 (P=1.4 x 10(-6)), rs4657247 in RGS5 at 1q23.3 (P=4.1 x 10(-6)), and rs7078071 in BTBD16 at 10q26.13 (P=4.5 x 10(-6)). This study is the first to conduct GWA of BD in individuals of AA and suggests that genetic variations that contribute to BD may vary as a function of ancestry.

Age transitions in the course of bipolar I disorder.

BACKGROUND: This analysis aimed to show whether symptoms of either pole change in their persistence as individuals move through two decades, whether such changes differ by age grouping, and whether age of onset plays an independent role in symptom persistence. METHOD: Participants in the National Institute of Mental Health (NIMH) Collaborative Depression Study (CDS) who completed at least 20 years of follow-up and who met study criteria for bipolar I or schizo-affective manic disorder, before intake or during follow-up, were divided by age at intake into youngest (18-29 years, n=56), middle (30-44 years, n=68) and oldest (>44 years, n=24) groups. RESULTS: The persistence of depressive symptoms increased significantly in the two younger groups. Earlier ages of onset were associated with higher depressive morbidity throughout the 20 years of follow-up but did not predict changes in symptom persistence. The proportions of weeks spent in episodes of either pole correlated across follow-up periods in all age groupings, although correlations were stronger for depressive symptoms and for shorter intervals. CONCLUSIONS: Regardless of age at onset, the passage of decades in bipolar illness seems to bring an increase in the predominance of depressive symptoms in individuals in their third, fourth and fifth decades and an earlier age of onset portends a persistently greater depressive symptom burden. The degree to which either depression or manic/hypomanic symptoms persist has significant stability over lengthy periods and seems to reflect traits that manifest early in an individual's illness.

Does major depressive disorder change with age?

BACKGROUND: The authors used results from a 20-year, high-intensity follow-up to measure the influence of ageing, and of age at onset, on the long-term persistence of symptoms in major depressive disorder (MDD). METHOD: Subjects who completed a 20-year series of semi-annual and then annual assessments with a stable diagnosis of MDD or schizo-affective disorder other than mainly schizophrenic (n=220) were divided according to their ages at intake into youngest (18-29 years), middle (30-44 years) and oldest (>45 years) groups. Depressive morbidity was quantified as the proportion of weeks spent in major depressive or schizo-affective episodes. General linear models then tested for effects of time and time x group interactions on these measures. Regression analyses compared the influence of age of onset and of current age. RESULTS: Analyses revealed no significant time or group x time effects on the proportions of weeks in major depressive episodes in any of the three age groups. Earlier ages of onset were associated with greater symptom persistence, particularly in the youngest group. The proportions of weeks ill showed intra-individual stability over time that was most evident in the oldest group. CONCLUSIONS: These results indicate that the persistence of depressive symptoms in MDD does not change as individuals move from their third to their fifth decade, from their fourth to their sixth decade, or from their sixth to their eighth decade. An early age of onset, rather than youth per se, is associated with greater morbidity over two decades.

The association between course of illness and subsequent morbidity in bipolar I disorder.

OBJECTIVE: We examined the relationship between certain bipolar I disorder clinical course variables over 5 years with outcome over the subsequent 5-year period. METHODS: Prospective observational follow-up data of 123 bipolar I subjects were analyzed. Predictive clinical variables included the frequency and direction of switches, and the quantity, polarity and length of affective periods. Outcome variables were an affective burden index (ABI) accounting for week-by-week severity and weeks hospitalized. Bivariate analyses guided the selection of predictors for multivariable analyses against the outcome variables. RESULTS: Affective burden index: while the number and direction of switches, the number of polyphasic episodes, weeks in hypomania/mania/mixed state, weeks in minor/major depression, weeks in at least marked affective syndrome, and weeks in any affective syndrome all had bivariate correlation (p<0.01) with the ABI, only weeks in hypomania/mania/mixed state and weeks in minor/major depression made significant contributions in the multivariable analysis (p<0.01) with the ABI. Weeks hospitalized: weeks in at least marked affective syndrome were significantly correlated with weeks hospitalized in bivariate analysis (p<0.01), and maintained a contribution to weeks hospitalized in the multivariable analysis (p<0.01). CONCLUSIONS: The quantity and severity of weeks in symptomatic affective states are possibly greater predictors of affective burden in bipolar I patients than the quantity and direction of affective switches.

Diagnosis-specific mortality. Primary unipolar depression and Briquet's syndrome (somatization disorder).

A 42-year follow-up of 76 women with Briquet's syndrome revealed no evidence of excess mortality. A carefully matched group of patients with primary unipolar depression had excess mortality in comparison both with the Briquet's syndrome group and with the Iowa population. Although one of the 30 patients with Briquet's syndrome with available death certificates died by suicide, the rate of death due to unnatural causes in the Briquet's syndrome group was not greater than that predicted by relevant population figures. These findings suggest that some psychiatric illnesses involve excess mortality while others do not. Reasons for this excess likewise may vary by diagnosis.

A blind family history study of Briquet's syndrome. Further validation of the diagnosis.

We undertook a blind family history study of Briquet's syndrome to complement earlier follow-up work by Perley and Guze. The same criteria were used in a chart review to select 49 Briquet's syndrome cases. One control group consisted of consecutive "non-Briquet hysteria" admissions and another of matched primary unipolar depressed cases. First-degree relatives of the Briquet's syndrome probands had significantly less affective disorder and more "complicated medical history" then either control group. The "non-Briquet hysteria" group contained more faily histories with instances of schizophrenia than either the Briquet's syndrome or effective disorder groups. These results provide additional validation of the Briquet's syndrome diagnosis.

The heritability of schizophrenia and schizoaffective disorder. A family study.

Ninety-one consecutively admitted patients with schizophrenia (n = 21), schizoaffective depression (n = 43), or psychotic depression (n = 27) entered a blind family study along with 36 never-ill controls. Though schizophrenia spectrum disorders clustered within families, they were not significantly more prevalent in the families of schizophrenic probands. In contrast, morbid risks for affective disorder clearly separated the families of psychotically depressed probands from the families of both schizophrenics and controls. Family study data for schizoaffective probands indicated links to both affective disorder and schizophrenia and suggested, as well, that a small number of patients with schizoaffective disorder may carry a genetic liability to both conditions.

Reliability of follow-up assessments of depressed inpatients.

Twenty-one depressed inpatients were followed up for six months after hospital admission. One rater assessed the patients at monthly intervals, and an independent rater assessed symptoms and treatment for the same period at the end of the six-month follow-up. Ratings of audiotapes of the monthly interviews by a third rater achieved excellent reliability. Fair to excellent agreement was also found between the monthly and six-month interviews. Reliability was lowest during the first month of the follow-up period. Unexpectedly, at the six-month interview more rather than fewer symptoms were reported for the most remote part of the follow-up interval. Our results suggest that at the six-month interview patients had reevaluated their functioning for the immediate postdischarge period.

DSM-III personality disorder diagnoses in a nonpatient sample. Demographic correlates and comorbidity.

Seven hundred ninety-seven first-degree relatives of normal controls and patients with a variety of psychiatric disorders were interviewed with the Diagnostic Interview Schedule and the Structured Interview for DSM-III Personality Disorders. Slightly more than one sixth of the sample received a personality disorder (PD) diagnosis, and of those with a PD, almost one fourth had more than one. The most prevalent diagnoses were mixed, passive-aggressive, antisocial, histrionic, and schizotypal PD. The demographic correlates and frequency of Axis I disorders in individuals with each specific PD were examined, and all but histrionic and passive-aggressive PDs had distinctive profiles.

The validity of a self-report questionnaire for diagnosing major depressive disorder.

Six hundred thirteen first-degree relatives of schizophrenics, depressives, and normal controls were interviewed with the Diagnostic Interview Schedule (DIS) and completed the Inventory to Diagnose Depression (IDD), a self-report scale to diagnose major depressive disorder (MDD). The current point prevalence of MDD was nearly identical according to the two measures (DIS, 2.8%; IDD, 2.6%). Diagnostic concordance varied according to the Interval between the evaluations. When the two measures were completed within two days of each other the agreement was as high as can be expected between two instruments with less than perfect reliability. We used a family study approach to examine validity and found that both the DIS and IDD cases of depression were two to three times more frequent in the relatives of depressed patients than the relatives of schizophrenics and controls.

Primary unipolar depression and the prognostic importance of delusions.

A consecutive series of inpatients with primary unipolar depression was categorized by the presence or absence of delusions as noted in the charts. The systematically obtained follow-up material contained in these charts showed that delusional patients had a relatively poor short-term outcome regardless of whether they received somatic treatment. Recovery rate increased with longer follow-up periods in both groups. In accord with this, a 40-year follow-up revealed no differences between delusional and nondelusional groups in terms of marital, residential, or occupational status, psychiatric symptoms, a final diagnosis of bipolar disorder, or death by suicide.

DSM-III schizophreniform disorder. Comparisons with schizophrenia and affective disorder.

We compared blind ratings of outcome and familial psychopathology across four diagnostic groups to test the validity of DSM-III schizophreniform disorder. Outcome ratings for schizophreniform disorder fell between those for affective disorder and those for schizophrenia. Outcome differences between schizophreniform and schizophrenic groups were no longer significant when patients who received somatic therapy during their index admission were excluded. Furthermore, schizophreniform probands had patterns of familial psychopathology that resembled those for schizophrenic probands more than those for affective disorder probands. In the combined group of schizophrenic and schizophreniform patients, longer illness durations at index admission predicted lower recovery rates. Our data suggests that a shorter specified duration may be appropriate in the definition of schizophreniform disorder.

Excess mortality in panic disorder. A comparison with primary unipolar depression.

We located 113 former inpatients with panic disorder 35 years after index admission. According to age- and sex-specific Iowa population figures, patients with panic disorder had significant excess mortality due to death by unnatural causes. Other studies suggest that secondary depression and alcoholism may have had a role in these deaths. Men with panic disorder also exhibited excess mortality due to circulatory system disease. In an age- and sex-matched patient group with primary unipolar depression, both men and women showed excess mortality. Suicide accounted for 20.0% and 16.2% of deaths in the panic disorder and primary depression groups, respectively. We conclude that panic disorder accounted for much of the excess mortality formerly noted in the "neuroses."

Major depression in a nonclinical sample. Demographic and clinical risk factors for first onset.

The relatives, controls, and spouses of affectively ill probands underwent diagnostic examinations on two occasions, 6 years apart. Of 965 subjects who had never been mentally ill when first examined, 11.8% had development of at least one episode of major depression as defined by the Research Diagnostic Criteria during the ensuing 6 years. Subjects younger than 40 years were three times more likely than older subjects to develop depression and women were approximately twice as likely as men to develop depression regardless of age. Marital disruption, a farm setting, and high educational achievement substantially increased the risk of depression among female subjects. Of 214 never-depressed subjects with a history of nonaffective mental disorder, 62 (29.0%) developed major depression. Age and sex were again powerful determinants. The course of prospectively observed secondary depression was more severe than that for primary depression.