William Coryell

Major depressive disorder: a prospective study of residual subthreshold depressive symptoms as predictor of rapid relapse.

BACKGROUND The study tested whether level of recovery from major depressive episodes (MDEs) predicts duration of recovery in unipolar major depressive disorder (MDD) patients. METHODS MDD patients seeking treatment at five academic centers were followed naturalistically for 10 years or longer. Patients were divided on the basis of intake MDE recovery into residual depressive symptoms (SSD; N=82) and asymptomatic (N=155) recovery groups. They were compared on time to first episode relapse/recurrence, antidepressant medication, and comorbid mental disorders. Recovery level was also compared to prior history of recurrent MDEs ( > 4 lifetime episodes) as a predictor of relapse/recurrence. RESULTS Residual SSD compared to asymptomatic recovery patients relapsed to their next MDE > 3 times faster (median=68 vs. 23 weeks) and to any depressive episode > 5 times faster (median=33 vs. 184 weeks). Residual SSD recovery status was significantly associated with early episode relapse (OR=3.65) and was stronger than history of recurrent MDEs (OR=1.64). Rapid relapse in the SSD group could not be attributed to higher comorbidity or lower antidepressant treatment. LIMITATIONS Although inter-rater agreement on weekly depressive symptom ratings was very high (ICC > 0.88), some error may exist in assigning recovery levels. Antidepressant treatments were recorded, but were not controlled. CONCLUSIONS MDE recovery is a powerful predictor of time to episode relapse/recurrence. Residual SSD recovery is associated with very rapid episode relapse which supports the idea that SSD is an active state of illness. Asymptomatic recovery is associated with prolonged delay in episode recurrence. These findings of this present study have important implications for the goals of treatment of MDD and for defining true MDE recovery.

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 × 10−6) and rs10193871 in NAP5 at 2q21.2 (P=9.8 × 10−6). For the AA sample, SNPs with the strongest statistical evidence for association included rs2111504 in DPY19L3 at 19q13.11 (P=1.5 × 10−6) and rs2769605 in NTRK2 at 9q21.33 (P=4.5 × 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 × 10−6), rs4657247 in RGS5 at 1q23.3 (P=4.1 × 10−6), and rs7078071 in BTBD16 at 10q26.13 (P=4.5 × 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.

The comparative clinical phenotype and long term longitudinal episode course of bipolar I and II: a clinical spectrum or distinct disorders?

BACKGROUND The present analyses were designed to compare the clinical characteristics and long-term episode course of Bipolar-I and Bipolar-II patients in order to help clarify the relationship between these disorders and to test the bipolar spectrum hypothesis. METHODS The patient sample consisted of 135 definite RDC Bipolar-I (BP-I) and 71 definite RDC Bipolar-II patients who entered the NIMH Collaborative Depression Study (CDS) between 1978 and 1981; and were followed systematically for up to 20 years. Groups were compared on demographic and clinical characteristics at intake, and lifetime comorbidity of anxiety and substance use disorders. Subsets of patients were compared on the number and type of affective episodes and the duration of inter-episode well intervals observed during a 10-year period following their resolution of the intake affective episode. RESULTS BP-I and BP-II had similar demographic characteristics and ages of onset of their first affective episode. Both disorders had more lifetime comorbid substance abuse disorders than the general population. BP-II had a significantly higher lifetime prevalence of anxiety disorders in general, and social and simple phobias in particular, compared to BP-I. Intake episodes of BP-I were significantly more acutely severe. BP-II patietns had a substantially more chronic course, with significantly more major and minor depressive episodes and shorter inter-episode well intervals. BP-II patients were prescribed somatic treatment a substantially lower percentage of time during and between affective episodes. LIMITATIONS BP-I patients with severe manic course are less likely to be retained in long-term follow-up, whereas the reverse might be true for BP-II patients who are significantly more prone to depression (i.e., patients with less inclination to depression and with good prognosis may have dropped out in greater proportions); this could increase the gap in long term course characteristics between the two samples. The greater chronicity of BP-II may be due, in part, to the fact that the patients were prescribed somatic treatments substantially less often both during and between affective episodes. CONCLUSIONS The variety in severity of the affective episodes shows that bipolar disorders, similar to unipolar disorders, are expressed longitudinally during their course as a dimensional illness. The similarities of the clinical phenotypes of BP-I and BP-II, suggest that BP-I and BP-II are likely to exist in a disease spectrum. They are, however, sufficiently distinct in terms of long-term course (i.e., BP-I with more severe episodes, and BP-II more chronic with a predominantly depressive course), that they are best classified as two separate subtypes in the official classification systems.

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.

Bipolar II. Combine or keep separate

Data on prior course, characteristics of index episode, and familial aggregation of patients with bipolar II disorder is discussed. The data supports the separation of this condition from both bipolar I and recurrent unipolar disorder.

Genomewide Linkage Analyses of Bipolar Disorder: A New Sample of 250 Pedigrees from the National Institute of Mental Health Genetics Initiative

We conducted genomewide linkage analyses on 1,152 individuals from 250 families segregating for bipolar disorder and related affective illnesses. These pedigrees were ascertained at 10 sites in the United States, through a proband with bipolar I affective disorder and a sibling with bipolar I or schizoaffective disorder, bipolar type. Uniform methods of ascertainment and assessment were used at all sites. A 9-cM screen was performed by use of 391 markers, with an average heterozygosity of 0.76. Multipoint, nonparametric linkage analyses were conducted in affected relative pairs. Additionally, simulation analyses were performed to determine genomewide significance levels for this study. Three hierarchical models of affection were analyzed. Significant evidence for linkage (genomewide P<.05) was found on chromosome 17q, with a peak maximum LOD score of 3.63, at the marker D17S928, and on chromosome 6q, with a peak maximum LOD score of 3.61, near the marker D6S1021. These loci met both standard and simulation-based criteria for genomewide significance. Suggestive evidence of linkage was observed in three other regions (genomewide P<.10), on chromosomes 2p, 3q, and 8q. This study, which is based on the largest linkage sample for bipolar disorder analyzed to date, indicates that several genes contribute to bipolar disorder.

Bipolar I: a five-year prospective follow-up.

We explored the course of bipolar I illness in 172 probands who were followed up prospectively for up to 5 years. Probands were grouped into three categories based on whether the symptoms of the index episode were only depressed, only manic, or mixed/cycling. Data were available for recovery from the index episode, subsequent relapse, and rates of recovery from the first prospective episode. Pure manic probands had a significantly faster rate of recovery (median, 6 weeks) than the mixed/cycling probands (median, 17 weeks), and the pure depressive probands had an intermediate rate (median, 11 weeks). After 5 years of follow-up the mixed/cycling patients continue to have the lowest cumulative probability of recovery from the index episode. Mixed/cycling probands also had a substantially faster time to relapse after recovery from the index episode compared with pure manic patients. For those patients who relapsed, the mixed/cycling patients had the lowest cumulative probability of recovery from the first prospectively observed episode. The treatment received by these patients is described and there is a discussion of how this treatment may have influenced the findings on course and outcome.

Residual Symptom Recovery From Major Affective Episodes in Bipolar Disorders and Rapid Episode Relapse/Recurrence

CONTEXT Both bipolar disorder type I and type II are characterized by frequent affective episode relapse and/or recurrence. An increasingly important goal of therapy is reducing chronicity by preventing or delaying additional episodes. OBJECTIVES To determine whether the continued presence of subsyndromal residual symptoms during recovery from major affective episodes in bipolar disorder is associated with significantly faster episode recurrence than asymptomatic recovery and whether this is the strongest correlate of early episode recurrence among 13 variables examined. DESIGN An ongoing prospective, naturalistic, and systematic 20-year follow-up investigation of mood disorders: the National Institute of Mental Health Collaborative Depression Study. SETTING Five academic tertiary care centers. PARTICIPANTS Two hundred twenty-three participants with bipolar disorder (type I or II) were followed up prospectively for a median of 17 years (mean, 14.1 [SD, 6.2] years). MAIN OUTCOME MEASURE Participants defined as recovered by Research Diagnostic Criteria from their index major depressive episode and/or mania were divided into residual vs asymptomatic recovery groups and were compared according to the time to their next major affective episodes. RESULTS Participants recovering with residual affective symptoms experienced subsequent major affective episodes more than 3 times faster than asymptomatic recoverers (hazard ratio, 3.36; 95% confidence interval, 2.25-4.98; P < .001). Recovery status was the strongest correlate of time to episode recurrence (P < .001), followed by a history of 3 or more affective episodes before intake (P = .007). No other variable examined was significantly associated with time to recurrence. CONCLUSIONS In bipolar disorder, residual symptoms after resolution of a major affective episode indicate that the individual is at significant risk for a rapid relapse and/or recurrence, suggesting that the illness is still active. Stable recovery in bipolar disorder is achieved only when asymptomatic status is achieved.

DSM-III personality disorders: Diagnostic overlap and internal consistency of individual DSM-III criteria

Abstract We rated the presence or absence of every DSM-III personality criteria in a cohort of 131 non-psychotic subjects. Ratings were based on the Structured Interview for DSM-III Personality Disorders (SIDP) which was administered to each patient and a knowledgable informant. Diagnositc overlap of the personality disorders (PD) was examined. Sensitivity, specificity, predictive value—positive and negative, and interrater reliability was calculated for each criteria item of each personality disorder. Problems in reliability of DSM-III personality disorders can be traced to specific criteria within those disorders that are associated with low reliability and/or low predictive value positive when compared to the other criteria used to define the personality disorder. Improvements are suggested. We were unable to demonstrate a significantly greater enhancement of reliability among criteria structures using a polythetic classification over those using monothetic classification despite a trend favoring the former. This study agrees with others that find a great deal of overlap between borderline PD and histrionic PD as defined in DSM-III. Passive-aggressive PD is very rare in the absence of some other PD. Paranoid and schizoid personality disorders were also rare though this may reflect the fact that individuals with these disorders rarely seek treatment.

The inventory to diagnose depression lifetime version

ABSTRACT— The lifetime version of the Inventory to Diagnose Depression (IDDL) is a 22‐item self‐report scale designed to diagnose a lifetime history of DSM‐III major depressive disorder (MDD). One hundred and sixty‐four first‐degree relatives of healthy control probands completed the IDDL and were interviewed with the Diagnostic Interview Schedule (DIS). The IDDL had good internal consistency (Cronbachs alpha = 0.92), split‐half reliability (Spearman‐Brown coefficient = 0.90), and all of the item total correlations were significant. The lifetime prevalence of MDD was nonsignificantly higher in the IDDL than the DIS (14.8% vs. 11.7%). Using the DIS as the criterion measure, the sensitivity of the IDDL was 74% and its specificity was 93% and the chance corrected agreement between the two measures was kappa = 0.60.