BP-I Disorder Research Articles

Further Evidence of the Diagnostic Utility of the Child Behavior Checklist for Identifying Pediatric Bipolar I Disorder.

Background:Pediatric bipolar (BP) disorder is a prevalent and highly morbid disorder. While structured diagnostic interviews have been developed to aid in the diagnosis of pediatric BP disorder, these tools are lengthy, costly and not widely available. One possible diagnostic aid is the Child Behavior Checklist (CBCL).Objective:To assess the diagnostic utility of the CBCL-BP profile to identify children with a diagnosis of BP-I disorder.Method:Subjects were derived from four independent data sets of children and adolescents with and without attention deficit hyperactivity disorder and BP-I. Subjects were recruited from pediatric and psychiatric clinics and the community. All subjects had structured clinical interviews with raters blinded to subject ascertainment status. We used an empirically derived profile from the CBCL consisting of an aggregate t-score from the Attention, Anxiety/Depression and Aggression subscales (CBCL-BP profile) to operationalize the presence or absence of BP symptoms. Receiver operating characteristic (ROC) curves were used to examine the ability of the CBCL-BP profile to identify children with and without a structured interview diagnosis of BP-I disorder.Results:The sample consisted of 661 subjects (mean age: 11.7 ± 3.3 years, 57% male and 94% Caucasian). In total, 20 percent of participants (n = 130) met structured interview criteria for a full diagnosis of BP-I disorder. The ROC analysis of the CBCL-BP profile yielded an area under the curve (AUC) of 0.91. A t-score of ≥ 195 on the CBCL-BP profile correctly classified 86% of subjects with BP-I disorder with 80% sensitivity, 87% specificity, 61% positive predictive value (PPV) and 95% negative predictive value (NPV).Conclusion:The CBCL-BP profile efficiently discriminated pediatric subjects with and without a structured interview diagnosis of BP-I disorder. Findings suggest that the CBCL-BP profile may be an efficient tool to help identify children who are very likely to suffer from BP-I disorder.

Mood reactivity and affective dynamics in mood and anxiety disorders.

The application of ecological momentary assessment (EMA) in community settings provides a powerful opportunity to obtain measures of emotional reactivity to daily life events, as well as emotional dynamics in real time. This investigation examines the association between emotional reactivity to daily events and emotional experience in mood and anxiety disorders in a large community-based sample. Two-hundred and 87 participants with a lifetime history of bipolar I disorder (BPI; n = 33), bipolar II disorder (BPII; n = 37), major depression (MDD; n = 116), anxiety disorders without a mood disorder (ANX; n = 36), and controls without a lifetime history of mood, anxiety, or substance use disorder (n = 65) completed a 2-week EMA evaluation period concerning mood states and daily events. Following positive events, individuals with BPI reported greater decreases in both sad and anxious mood than did controls, and individuals with MDD experienced greater decreases in anxious mood. Following negative events, the BPII, MDD, and ANX (but not BPI) groups experienced greater increases in anxious mood, with no group differences in sad mood. Greater variability and instability were observed for sad mood in the BPII and MDD groups, and greater variability and instability was observed for anxious mood in all of the mood/anxiety groups. However, no group differences were observed for the inertia of sad or anxious moods. The findings demonstrate differences in emotional reactivity to daily events as well as the general affective dynamics of emotional states among individuals with mood or anxiety disorders, with potential specificity for BPI disorder relative to other disorders. Emotional variability and instability may constitute a nonspecific characteristic of both mood and anxiety disorders. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

Further evidence of high level of persistence of pediatric bipolar-I disorder from childhood onto young adulthood: a five-year follow up.

Background:Pediatric bipolar (BP)-I disorder affects a sizeable minority of children and is associated with high levels of morbidity. Relatively few studies have assessed the persistence of the disorder over time.Objective:The main aim of this study was to extend our findings from our 4-year follow-up study examining rates of persistence of pediatric BP-I disorder onto late adolescent years and young adulthood 5 years after our original study.Methods:We conducted a 1-year extension to our original prospective study of 78 youth, ages six to 17 years, with BP-I disorder at ascertainment, who were followed up into their adolescent and young adult years (14.9 ± 3.8). All subjects were comprehensively assessed with structured diagnostic interviews and psychosocial, educational, and treatment history assessments.Results:Of the 78 BP-I participating youth, 68 were re-accessioned one year following the 4-year follow-up study, thus effectively 5 years since the original study. Of these, 63% continued to meet full (50%) or subthreshold (13%) diagnostic criteria for BP-I and 18% continued to have full or subthreshold major depressive disorder. Only 19% of BP-I youth were euthymic at the 5-year follow up.Discussion:This 1-year extension study further documents the high level of persistence of pediatric BP-I from childhood onto late adolescence and young adulthood. The results provide compelling evidence of the morbidity and dysfunction associated with this disorder and its many forms.Clinical significance:This study adds to a small amount of literature on the persistence of pediatric BP disorder and the critical need for early identification and intervention.

Assessment of first and second degree relatives of individuals with bipolar disorder shows increased genetic risk scores in both affected relatives and young At-Risk Individuals.

Recent studies have revealed the polygenic nature of bipolar disorder (BP), and identified common risk variants associated with illness. However, the role of common polygenic risk in multiplex families has not previously been examined. The present study examined 249 European‐ancestry families from the NIMH Genetics Initiative sample, comparing subjects with narrowly defined BP (excluding bipolar II and recurrent unipolar depression; n = 601) and their adult relatives without BP (n = 695). Unrelated adult controls (n = 266) were from the NIMH TGEN control dataset. We also examined a prospective cohort of young (12–30 years) offspring and siblings of individuals with BPI and BPII disorder (at risk; n = 367) and psychiatrically screened controls (n = 229), ascertained from five sites in the US and Australia and assessed with standardized clinical protocols. Thirty‐two disease‐associated SNPs from the PGC‐BP Working Group report (2011) were genotyped and additive polygenic risk scores (PRS) derived. We show increased PRS in adult cases compared to unrelated controls (P = 3.4 × 10−5, AUC = 0.60). In families with a high‐polygenic load (PRS score ≥32 in two or more subjects), PRS distinguished cases with BPI/SAB from other relatives (P = 0.014, RR = 1.32). Secondly, a higher PRS was observed in at‐risk youth, regardless of affected status, compared to unrelated controls (GEE‐χ2 = 5.15, P = 0.012). This report is the first to explore common polygenic risk in multiplex families, albeit using only a small number of robustly associated risk variants. We show that individuals with BP have a higher load of common disease‐associated variants than unrelated controls and first‐degree relatives, and illustrate the potential utility of PRS assessment in a family context. © 2015 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics Published by Wiley Periodicals, Inc.

Alterations of cerebral glutamate in the euthymic state of patients with bipolar disorder

The pathophysiology of bipolar disorder (BD) mostly remains unclear. However, some findings argue for a dysfunction in glutamatergic neurotransmission in BD. Proton magnetic resonance spectroscopy at 3T was used to determine glutamate concentrations in the anterior cingulate cortex (ACC) and the hippocampus (HC) of euthymic outpatients with BP-I disorder and age- and sex-matched healthy controls. In patients with BD, glutamate concentrations were significantly increased in the ACC and decreased in the HC compared with concentrations in controls. Significant group differences were also measured for N-acetyl aspartate and choline; no differences were found for other metabolites examined. An inverse correlation was observed for glutamate concentrations in the ACC and number of episodes. The findings of the study add to the concept of abnormalities in glutamatergic regulation in the ACC and HC in patients with BD.

Test–retest reliability of a new questionnaire for the retrospective assessment of long-term lithium use in bipolar disorder

BackgroundThe identification of predictors of treatment response holds tremendous potential for the improvement of clinical outcomes in bipolar disorder (BP). The goal of this project is to evaluate the test–retest reliability of a new clinical tool, the Lithium Questionnaire (LQ), for the retrospective assessment of long-term lithium use in research participants with BP. MethodsTwenty-nine individuals with BP-I (n=27), major depression (n=1), or schizoaffective disorder (n=1) were recruited for participation. The LQ was administered to all participants at two time-points, spaced 17 months apart on average, and used to determine each subject׳s score on the Retrospective Criteria of Long-Term Treatment Response in Research Subjects with Bipolar Disorder Scale, or the Alda Scale. Scores were confirmed through a best-estimate procedure, and test–retest reliability (intra-class correlation coefficient [ICC]) of the LQ was calculated. ResultsThe correlation between the total Alda Scale scores at the two time-points was in the moderate range (ICC=0.60). Relevant clinical factors such as age or presence of Axis I psychiatric comorbidity did not influence the reliability. LimitationsThe validity of the LQ was not examined. Inclusion of two participants with non-BP diagnoses may have affected the LQ׳s reliability, but re-analysis of our data after exclusion of these participants did not influence the reliability. The absence of measures of mood and cognition at time of LQ may be a limitation of this work. ConclusionsThe LQ holds promise for the standardization of the retrospective assessment of long-term treatment in BP.

Short-term antidepressant treatment of bipolar depression: Are ISBD recommendations useful in clinical practice?

ObjectivesThe study aimed to test the effectiveness of the ISBD Guidelines for short-term AD treatment of BP depression. MethodsThe study sample included 255 patients with mood disorders (154 UP, 49 BP-I, 52 BP-II). Response was defined as a HDRS21 total score<7 at 12 weeks of treatment and remission as a ≥50% reduction of baseline HDRS21 total score sustained for 8 weeks. ResultsResponse was achieved by 64.9% of patients with UP disorder, 75.5% of patients with BP-I disorder and 75.0% with BP-II disorder without significant differences (χ²=3.0, p=0.219). The remission rate did not differ significantly among groups (χ²=3.8, p=0.151). The dropout rate was significantly higher for patients with UP (18.2%) than for patients with BP-I (2%) and BP-II (7.7%) disorder (χ²=10.1, p=0.006). Concerning AD safety, one patient with BP-I depression committed a suicide attempt and AD-emerging switch was observed in 2.9% of patients, 2 with BP-I and 1 with BP-II disorder. LimitationsThe observational nature of the study and unblinded outcomes assessment. ConclusionsOur findings confirm the usefulness of ISBD Guidelines for short-term AD treatment of BP depression. These patients appear to have similar response and remission rate to those observed in UP depression and do not exhibit significant switch rates or risk of suicide. Our results are limited to patients with pure bipolar depression (excluding those with broadly defined mixed states), treated with ADs-mood stabilizers combination. We suggest to partially modify ISBD Recommendations 1 and 4, to include potential responders and to improve safety.

Further evidence that severe scores in the aggression/anxiety-depression/attention subscales of child behavior checklist (severe dysregulation profile) can screen for bipolar disorder symptomatology: a conditional probability analysis

BackgroundPrevious work shows that children with high scores (2SD, combined score≥210) on the Attention Problems, Aggressive Behavior, and Anxious-Depressed (A-A-A) subscales of the Child Behavior Checklist (CBCL) are more likely than other children to meet criteria for bipolar (BP)-I disorder. However, the utility of this profile as a screening tool has remained unclear. MethodsWe compared 140 patients with pediatric BP-I disorder, 83 with attention deficit hyperactivity disorder (ADHD), and 114 control subjects. We defined the CBCL-Severe Dysregulation profile as an aggregate cutoff score of≥210 on the A-A-A scales. Patients were assessed with structured diagnostic interviews and functional measures. ResultsPatients with BP-I disorder were significantly more likely than both control subjects (Odds Ratio [OR]: 173.2; 95% Confidence Interval [CI], 21.2 to 1413.8; P<0.001) and those with ADHD (OR: 14.6; 95% CI, 6.2 to 34.3; P<0.001) to have a positive CBCL-Severe Dysregulation profile. Receiver Operating Characteristics analyses showed that the area under the curve for this profile comparing children with BP-I disorder against control subjects and those with ADHD was 99% and 85%, respectively. The corresponding positive predictive values for this profile were 99% and 92% with false positive rates of<0.2% and 8% for the comparisons with control subjects and patients with ADHD, respectively. LimitationsNon-clinician raters administered structured diagnostic interviews, and the sample was referred and largely Caucasian. ConclusionsThe CBCL-Severe Dysregulation profile can be useful as a screen for BP-I disorder in children in clinical practice.

Re-examining the risk for switch from unipolar to bipolar major depressive disorder in youth with ADHD: A long term prospective longitudinal controlled study

BackgroundRecent studies have identified subthreshold forms of bipolar (BP)-I disorder and deficits in emotional regulation as risk factors for bipolar disorder in youth. The primary aim of this study was to investigate whether emotional dysregulation and subthreshold forms of BP-I disorder increase the risk for BP switches in ADHD youth with non-bipolar MDD. MethodsWe used data from two large controlled longitudinal family studies of boys and girls with and without ADHD. Subjects (N=522) were followed prospectively and blindly over an average follow up period of 11.4 years. Comparisons were made between ADHD youth with unipolar major depression (MDD) who did (N=24) and did not (N=79) switch to BP-I disorder at follow-up. ResultsThe rate of conversion to BP-I disorder at follow up was higher in MDD subjects with subthreshold BP-I disorder at baseline compared to those without (57% vs. 21%; OR=9.57, 95% CI=1.62−56.56, p=0.013) and in MDD subjects with deficient emotional self-regulation (OR=3.54, 95% CI=1.08−11.60, p=0.037). LimitationsThe sample was largely Caucasian, so these results may not generalize to minority groups. The sample of youth with SED was small, which limited the statistical power for some analyses. ConclusionsSwitches from unipolar MDD to BP-I disorder in children with ADHD and MDD were predicted by baseline subthreshold BP-I disorder symptoms and baseline deficits in emotional regulation. More work is needed to assess whether these risk factors are operant outside the context of ADHD.

Does sex moderate the clinical correlates of pediatric bipolar-I disorder? Results from a large controlled family-genetic study

BackgroundSince little is known as to whether sex differences affect the clinical presentation of pediatric BP-I disorder, it is an area of high clinical, scientific and public health relevance. MethodsSubjects are 239 BP-I probands (65 female probands, 174 male probands) and their 726 first-degree relatives, and 136 non-bipolar, non-ADHD control probands (37 female probands, 99 male probands) and their 411 first-degree relatives matched for age and sex. We modeled the psychiatric and cognitive outcomes as a function of BP-I status, sex, and the BP-I status-gender interaction. ResultsBP-I disorder was equally familial in both sexes. With the exception of duration of mania (shorter in females) and number of depressive episodes (more in females), there were no other meaningful differences between the sexes in clinical correlates of BP-I disorder. With the exception of a significant sex effect for panic disorder and a trend for substance use disorders (p=0.05) with female probands being at a higher risk than male probands, patterns of comorbidity were similar between the sexes. Despite the similarities, boys with BP-I disorder received more intensive and costly academic services than girls with the same disorder. LimitationsSince we studied children referred to a family study of bipolar disorder, our findings may not generalize to clinic settings. ConclusionsWe found more similarities than differences between the sexes in the personal and familial correlates of BP-I disorder. Clinicians should consider bipolar disorder in the differential diagnosis of both boys and girls afflicted with symptoms suggestive of this disorder.

Personal and familial correlates of bipolar (BP)-I disorder in children with a diagnosis of BP-I disorder with a positive child behavior checklist (CBCL)-severe dysregulation profile: A controlled study

BackgroundAlthough the DSM-IV provides explicit criteria for the diagnosis of BP-I disorder, this is a complex diagnosis that requires high levels of clinical expertise. Previous work shows children with a unique profile of the CBCL of high scores (2SD) on the attention problems (AP), aggressive behavior (AGG), and anxious-depressed (AD) (A–A–A) subscales are more likely than other children to meet criteria for BP-I disorder in both epidemiological and clinical samples. However, since not all BP-I disorder children have a positive profile questions remain as to its informativeness, particularly in the absence of an expert diagnostician. MethodsAnalyses were conducted comparing personal and familial correlates of BP-I disorder in 140 youth with a structured interview and an expert clinician based DSM-IV diagnosis of BP-I disorder with (N=80) and without (N=60) a positive CBCL- Severe Dysregulation profile, and 129 controls of similar age and sex without ADHD or a mood disorder. Subjects were comprehensively assessed with structured diagnostic interviews and wide range of functional measures. We defined the CBCL-severe dysregulation profile as an aggregate cut-off score of ≥210 on the A–A–A scales. ResultsBP-I probands with and without a positive CBCL-severe dysregulation profile significantly differed from Controls in patterns of psychiatric comorbidity, psychosocial and psychoeducational dysfunction, and cognitive deficits, as well as in their risk for BP-I disorder in first degree relatives. LimitationsBecause the sample was referred and largely Caucasian, findings may not generalize to community samples and other ethnic groups. ConclusionA positive CBCL-severe dysregulation profile identifies a severe subgroup of BP-I disorder youth.

Further evidence that pediatric-onset bipolar disorder comorbid with ADHD represents a distinct subtype: Results from a large controlled family study

We used familial risk analysis to clarify the diagnostic comorbidity between pediatric BP-I disorder and ADHD, testing the hypothesis that pediatric-BP-I disorder comorbid with ADHD represents a distinct subtype. Structured diagnostic interviews were used to obtain DSM-IV psychiatric diagnoses on first-degree relatives (n = 726) of referred children and adolescents satisfying diagnostic criteria for BP-I disorder (n = 239). For comparison, diagnostic information on the first-degree relatives (N = 511) of non-bipolar ADHD children (N = 162) and the first degree relatives (N = 411) of control children (N = 136) with neither ADHD nor BP-I disorder were examined. BP-I disorder and ADHD in probands bred true irrespective of the comorbidity with the other disorder. We also found that the comorbid condition of BP-I disorder plus ADHD also bred true in families, and the two disorders co-segregated among relatives. This large familial risk analysis provides compelling evidence that pediatric BP-I disorder comorbid with ADHD represents a distinct familial subtype.

A 16-Year Prospective Study of Prodromal Features Prior to BPI Onset in Well Amish Children

Longitudinal research of well Amish children over 16 years to identify the pattern and frequency of prodromal symptoms/behaviors associated with onset of BPI disorder during childhood or adolescence. Parental informants were interviewed annually using structured and semi-structured interviews to record medical, developmental and behavioral/symptomatic data for their children in two samples. The bipolar sample had 115 children with a BPI parent. The control sample had 106 children of well parents, with and without a positive family history for mood disorders. A panel of clinicians assigned risk ratings independently and blind to family relations. Eight children, age 13 or older, onset with BPI in the bipolar sample compared with one in the control sub-sample (well parent of a BPI sibling). The specific "pre-school" behaviors/symptoms that most identified children with BPI from well children in control samples were: sensitivity, crying, hyper-alertness, anxiety/worry and somatic complaints. During school years, parents reported mood (sad) and energy changes (low not high) decreased sleep and fearfulness as key symptoms. The sample of 9 BPI onsets is small. However, a variable age of onset means many children remain at risk. Although not statistically significant, 34.6% of the bipolar sample youngsters carry risk ratings compared to 15.2% among controls. The miniclusters of prodromal features that emerged pre-school (ages 1-6), were "episodic" through childhood (7-12) and appeared to mimic adult recurrent illness. Prepubertal onset with mania did not occur. The pattern of prodromal symptoms has clinical relevance for its potential predictive value for onset with BPI disorder and early intervention.

High level of persistence of pediatric bipolar-I disorder from childhood onto adolescent years: A four year prospective longitudinal follow-up study

ObjectiveTo examine the longitudinal course of pediatric bipolar (BP)-I disorder in youth transitioning from childhood into adolescence. MethodsWe conducted a four year prospective follow-up study of 78 youth with BP-I disorder 6–17 years old at ascertainment followed up into adolescent years (13.4 ± 3.9 years). All subjects were comprehensively assessed with structured diagnostic interviews, neuropsychological testing, psychosocial, educational and treatment history assessments. BP disorder was considered persistent if subjects met full criteria for DSM-IV BP-I disorder at follow-up. ResultsOf 78 BP-I participating youth subjects, 57 (73.1%), continued to meet full diagnostic criteria for BP-I Disorder. Of those with a non-persistent course, only 6.4% (n = 5) were euthymic (i.e., syndromatic and symptomatic remission) at the 4-year follow-up and were not receiving pharmacotherapy for the disorder. The other non-persistent cases either continued to have subthreshold BP-I disorder (n = 5, 6.4%), met full (n = 3, 3.8%) or subthreshold (n = 1, 1.3%) criteria for major depression, or were euthymic but were treated for the disorder (n = 7, 9.0%). Full persistence was associated with higher rates of major depression and disruptive behavior disorders at the follow-up assessment and higher use of stimulant medicines at the baseline assessment. Non-Peristent BP-I was also characterized by high levels of dysfunction and morbidity. ConclusionsThis four year follow-up shows that the majority of BP-I disorder youth continue to experience persistent disorder into their mid and late adolescent years and its persistence is associated with high levels of morbidity and disability. Persistence of subsyndromal forms of bipolar disorder was also associated with dysfunction and morbidity.

PW01-12 - Two or three age-of-onset groups in bipolar I disorder? Findings of commingling analysis in Romanian and German bipolar I patients

BackgroundAge-of-onset (AO) seems to be a phenotypic variable with a strong genetic component and therefore useful in molecular analysis of bipolar disorder (BP). A debate about the cut-off point for defining early AO has developed over the last few years. Using an Expectation-Maximization algorithm Bellivier et al. (2001) found the best fit for a model with three onset-groups, proposing the age 20-21 as cut-off for early onset, while using the same algorithm Kennedy et al. (2005) found the best fit for a two onset-group model with age 40 as cut-off with an incidence peak for mania in the age-band 21-25. Based on segregation analysis, we proposed a two AO-group model with cut-off age 25 for early onset (Grigoroiu-Serbanescu et al. 2001). The present study aimed at investigating the best AO-model in 500 Romanian BPI and 1458 German BPI patients using commingling analysis (SAGEv6.01-software) (Elston et al, 2009). The best model was selected according to Akaike's Information Criterion (AIC).ResultsThe two AO-group and three AO-group models provided similar AIC-values both in the Romanian and the German sample. The Romanian early-onset group (40% cases) had means around 18 years, SDs=6-7, while in the German early-onset group the mean AO was around 20 years (SDs=9-11) (50% cases). Thus the cut-off for early-onset (X +1SD) was different.ConclusionOur results overlapped with the findings of Kennedy et al (2005) showing that two-curve and three-curve AO mixtures similarly fit the AO-distribution in BPI disorder and the cut-offs for early-onset differ by sample.

Risk for switch from unipolar to bipolar disorder in youth with ADHD: A long term prospective controlled study

BackgroundTo investigate whether ADHD is a risk factor for switches from unipolar to bipolar disorder over time. MethodsData from two large controlled longitudinal family studies of boys and girls with and without ADHD and their siblings were used. Subjects (n=168) were followed prospectively and blindly over an average follow-up period of 7 years. Comparisons were made between youth with unipolar major depression who did and did not switch to full or subthreshold BP-I disorder at the follow-up assessment. Subjects were assessed at baseline and follow-up on multiple domains of functioning. Positive family history of parental psychiatric disorders was also compared between groups. ResultsADHD was associated with a significantly higher risk for switches from unipolar to bipolar disorder (28% versus 6%; z=2.80, p=0.005). In subjects with ADHD, switches from unipolar to bipolar disorder were predicted by baseline comorbid conduct disorder, school behavior problems, and a positive family history of parental mood disorder. LimitationsPsychosis was an exclusionary criterion in the original ascertainment of the studies of ADHD probands, so we were unable to test this as a predictor of switching to BPD. ConclusionsADHD is a risk factor for switches from unipolar to bipolar disorder, and switches could be predicted by the presence of baseline conduct disorder, school behavior problems, and a positive family history of a mood disorder in a parent. These characteristics can aid clinicians in their treatment of youth with MDD.

Suicidal events and accidents in 216 first-episode bipolar I disorder patients: Predictive factors

Background Risks of life-threatening behaviors are high among bipolar disorder (BPD) patients, but early rates and associated risk factors for suicides and accidents remain ill-defined. Methods We assessed 216 DSM-IV BP-I patients prospectively for 4.2 years from first-lifetime hospitalization, using ordinal logistic-regression to estimate risks and associated demographic and clinical factors among risk-groups with: [1] no suicidal ideation, acts, or accidents, [2] suicidal ideation only, [3] suicides and attempts, [4] accidents, and [5] both suicidal acts and accidents. Results Suicidal thoughts or acts were identified in 127/216 subjects/4.2 years (14%/year), including suicidal ideation in 88 (9.7%/year), and acts in 39 (4.3%/year: 38 attempts [17.6%/year], 1 suicide [0.11%/year]); 87% of acts occurred within a year of a first-episode. Life-threatening accidents occurred in 20 cases (2.2%/year) with a mean latency of 3.8 years, including 12 with suicidal ideation or attempts (60% co-occurrence of accidents and suicidality); alcohol was implicated in 25% of accidents. The 53 cases of violent behaviors (5.84%/year) included a fatal car-wreck and a suicide, for a mortality risk of 0.22%/year (2/216/4.2 years). Suicidality was associated with initial mixed-state, proportion of follow-up weeks in mixed-states or depression, and prior suicide attempts; accidents were associated selectively with initial mania or psychosis, later mania or hypomania, and alcohol abuse. Violent acts also were associated with use of more psychotropic medicines/person, and with use of antipsychotics or sedative-anxiolytics. Limitations Treatment was clinical and uncontrolled, illness relatively severe, and statistical power limited. Conclusions Early in BP-I disorder, risks of suicidal acts and accidents were high, inter-related, and associated with particular types of initial and later morbidity, suggesting some predictability and potential for preventive intervention.

Diagnostic conversion from depression to bipolar disorders: results of a long-term prospective study of hospital admissions

Objectives: To analyse the time course and some risk factors for a diagnostic change from major depression to bipolar disorders (BP) over an average of 20 years from the onset of the disorders. Methods: Patients (406) with major mood disorders hospitalised at some time between 1959 and 1963 were followed-up until 1985. The analysis also included the course prior to hospitalisation. Survival analyses and Cox regression models were applied. Results: A diagnostic change from depression to bipolar I occurred in about 1% of the patients per year and to bipolar II disorders in about 0.5% per year. Risk factors for a change from depression to BP-I disorder were male sex and an early onset of the disorder; risk factors for a change from depression to BP-II disorder were female sex, a later onset of the disorder and a positive family history of mania. Conclusions: Across the entire lifetime, every new episode of depression brings a new risk for mania; more than half of our severe mood disorder cases became bipolars. The risk of depression developing into bipolar disorder remains constant lifelong. Limitations: The diagnostic classification of ICD-9 met RDC criteria for bipolar disorder in only 90% of cases. Part of the data collected in retrospect may be less reliable; the prospective data were only collected every 5 years from 1965 to 1985 using multiple sources; mild manifestations between the follow-ups may have been partially missed. The sample of subsequent hospital admissions for major depression and mania represents a severe group of patients and generalisations to ambulatory cases may not be possible. Not all risk factors for diagnostic conversion described in the literature could be assessed in this study.

The 5HT1Dβ Receptor Gene in Bipolar Disorder: A Family-based Association Study

The serotonin (5HT) receptor genes are considered good candidates for Major Depression (MD), Bipolar Disorder (BP), and Obsessive-Compulsive Disorder (OCD). The 5HT1Dβ receptor gene has at least three polymorphisms known: G861C, T-261G, and the functional T371G (Phe-124-Cys). The aim of this study was to investigate for the presence of linkage disequilibrium between the 5HT1Dβ receptor gene and BP. Two hundred and ninety probands with DSM-IV BPI, BPII, or Schizoaffective Disorder (Bipolar type) with their living parents were recruited. Genotyping data for the G861C and T371G polymorphisms were analyzed using the Transmission Disequilibrium Test (TDT). One hundred and sixty triads were informative for the TDT on the G861C polymorphism, which showed no preferential transmission of either allele (chi-square = 0.438, df = 1, p = .508). Only four triads were suitable for the analysis on the T371G variant, with the T allele transmitted once and the G allele transmitted four times to the affected. These findings validate further the results of pharmacological studies excluding a direct involvement of the 5HT1Dβ receptor in the pathogenesis of BP. Further investigations combining genetic and pharmacological strategies are warranted.

Linkage analysis of bipolar illness with X‐chromosome DNA markers: A susceptibility gene in Xq27‐q28 cannot be excluded

Transmission studies have supported the presence of a susceptibility gene for bipolar (BP) illness on the X-chromosome. Initial linkage studies with color blindness (CB), glucose-6-phosphate dehydrogenase (G6PD) deficiency, and the blood coagulation factor IX (F9) have suggested that a gene for BP illness is located in the Xq27-q28 region. We tested linkage with several DNA markers located in Xq27-q28 in 2 families, MAD3 and MAD4, that previously were linked to F9 and 7 newly ascertained families of BP probands. Linkage was also examined with the gene encoding the alpha 3 subunit of the gamma-amino butyric acid receptor (GABRA3), a candidate gene for BP illness located in this region. The genetic data were analyzed with the LOD score method using age-dependent penetrance of an autosomal dominant disease gene and narrow and broad clinical models. In MAD3 and MAD4 the multipoint LOD score data suggested a localization of a BPI gene again near F9. In the 7 new families the overall linkage data excluded the Xq27-q28 region. However, if the families were grouped according to their proband's phenotype BPI or BPII, a susceptibility gene for BPI disorder at the DXS52-F8 cluster could not be excluded.