Familial Bipolar Disorder Research Articles

Sequence analysis of ADARB1 gene in patients with familial bipolar disorder

Background: The ADARB1 gene is located in 21q22.3 region, previously linked to familial bipolar disorder, and its product has a documented action in the editing of the pre-mRNA of glutamate receptor B subunit. Dysfunction of glutamatergic neurotransmission could play an important role in the patophysiology of bipolar disorder (BD). Glutamate excitatory neurotransmission regulation is a possible mechanism of the initial effect of anticonvulsants in regulating mood. Methods: To investigate the hypothesis of an involvement of ADARB1 gene in the BD, the ADARB1 cDNA has been cloned and sequenced in seven selected bipolar I disorder patients with evidence of familiarity of mood disorders. A detailed investigation of the gene nucleotide sequence in the open reading frame has been performed. Results: No alteration in the sequence of the ADARB1 gene cDNA was found in any patient, except a common neutral polymorphism in three out of seven patients. Conclusions: Mutations in ADARB1 gene are not commonly associated with bipolar I disorder, therefore other genes in the 21q22 region could be associated with bipolar illness in some families, likely in the context of a multifactorial transmission model.

Association of rapid mood switching with panic disorder and familial panic risk in familial bipolar disorder.

Comorbid bipolar and panic disorders aggregate in families. A phenotypic trait shared by both disorders is the sudden shift in affect observed in panic attacks and some rapid cycling states. The authors investigated whether comorbidity of bipolar disorder and panic disorder is associated with rapid mood switching in families with a high rate of bipolar disorder. Six hundred six subjects with bipolar disorder from the NIMH Bipolar Disorder Genetics Initiative were included in the study. Logistic regression analysis was used to analyze rapid mood switching as a function of panic disorder diagnosis, sex, and familial risk for panic. Familial panic and the diagnosis of panic disorder in an individual subject increased the odds for rapid mood switching. The familial effect persisted when individuals with panic disorder were excluded from the analysis. Panic and rapid mood switching occurring together in familial bipolar disorder may define a useful subphenotype for future studies.

Familial bipolar disorder and multiple sclerosis: a three-generation HLA family study

The coexistence of bipolar disorder (BD) and multiple sclerosis (MS) is well known. Manic symptoms may represent initial symptoms of MS, at least in some cases, and follow the MS-HLA phenotype frequencies. The purpose of this study was to examine the possible relation of BD and MS based on an HLA family study of a woman with BD and comorbid MS, with family history of BD. Five members of the family from three generations (the patient, her mother, her brother, and her two daughters) were examined regarding the two disorders and the HLA class I and II specificities, performed by serology and molecular techniques. Her deceased father, her brother, and her older daughter suffered from BD. Moreover, in her brother, BD and MS comorbidity was diagnosed. The three affected members and the nonaffected grandmother share the same class I and II, HLA-A2, B18, CW8, DR2, DQ1 haplotype. The shared class II, HLA-DR2, DQ1 haplotype among affected individuals, which is well known to be associated with MS in Caucasians, suggests a possible susceptibility locus for BD, mapped on chromosome 6, very close to the HLA region, underlying the clinical comorbidity of the two disorders.

Decreased N-Acetylaspartate in children with familial bipolar disorder

BackgroundRelatively low levels of brain N-acetylaspartate, as measured by magnetic resonance spectroscopy, may indicate decreased neuronal density or viability. Dorsolateral prefrontal levels of N-acetylaspartate have been reported to be decreased in adults with bipolar disorder. We used proton magnetic resonance spectroscopy to investigate dorsolateral prefrontal N-acetylaspartate levels in children with familial bipolar disorder. MethodsSubjects were 15 children and adolescents with bipolar disorder, who each had at least one parent with bipolar disorder, and 11 healthy controls. Mean age was 12.6 years for subjects and controls. Subjects were allowed to continue current medications. Proton magnetic resonance spectroscopy at 3-Tesla was used to study 8 cm3 voxels placed in left and right dorsolateral prefrontal cortex. ResultsBipolar subjects had lower N-acetylaspartate/Creatine ratios only in the right dorsolateral prefrontal cortex (p < .02). No differences in myoinositol or choline levels were found. ConclusionsChildren and adolescents with bipolar disorder may have decreased dorsolateral prefrontal N-acetylaspartate, similar to adults with BD, indicating a common neuropathophysiology. Longitudinal studies of at-risk children before the onset and during the early course of bipolar disorder are needed to determine the role of prefrontal N-acetylaspartate as a possible risk marker and/or indication of early bipolar illness progression.

Evidence that a single nucleotide polymorphism in the promoter of the G protein receptor kinase 3 gene is associated with bipolar disorder.

In a genome-wide linkage survey, we have previously shown evidence suggesting that the chromosome 22q12 region contains a susceptibility locus for bipolar disorder (BPD). Two independent family sets yielded lod scores suggestive of linkage at markers in this region near the gene G protein receptor kinase 3 (GRK3). GRK3 is an excellent candidate risk gene for BPD since GRK3 is expressed widely in the brain, and since GRKs play key roles in the homologous desensitization of G protein-coupled receptor signaling. We have also previously shown GRK3 expression to be induced by amphetamine in an animal model of mania using microarray-based expression profiling. To identify possible functional mutations in GRK3, we sequenced the putative promoter region, all 21 exons, and intronic sequence flanking each exon, in 14-22 individuals with BPD. We found six sequence variants in the 5'-UTR/promoter region, but no coding or obvious splice variants. Transmission disequilibrium analyses of one set of 153 families indicated that two of the 5'-UTR/promoter variants are associated with BPD in families of northern European Caucasian ancestry. A supportive trend towards association to one of these two variants (P-5) was then subsequently obtained in an independent sample of 237 families. In the combined sample, the P-5 variant had an estimated allele frequency of 3% in bipolar subjects, and displayed a transmission to non-transmission ratio of 26 : 7.7 (chi(2)=9.6, one-sided P value=0.0019). Altogether, these data support the hypothesis that a dysregulation in GRK3 expression alters signaling desensitization, and thereby predisposes to the development of BPD.

Depressive mixed state frequency: age/gender effects.

Depressive mixed state (DMX), a major depressive episode (MDE) combined with few manic/hypomanic symptoms, is understudied. Age and gender are important variables in mood disorders. The aim of the present study was to determine whether age and gender had any effect on the frequency of DMX. Consecutive unipolar (n = 144) and bipolar II (n = 218) drug-free MDE out-patients were interviewed with the Structured Clinical Interview for DSM-IV when presenting for MDE treatment. The presence of hypomanic symptoms during the index MDE was assessed systematically. Depressive mixed state was defined as a MDE with three or more concurrent hypomanic symptoms (DMX3), following previous reports. Associations were tested by logistic regression. The results showed that the DMX3 frequency was 43.9% and that it affected more females than males. Frequency decreased with age. The lower frequency with age was related to the lower frequency of bipolar II disorder with age. Bipolar disorder family history of DMX3 patients did not change with age. In conclusion, the frequency of DMX3 was high and related to age. The high frequency of DMX3 supports the clinical usefulness of the definition, as well as observations that antidepressants may worsen its hypomanic symptoms, whereas antipsychotics and mood stabilisers may treat them. A bipolar vulnerability seems to be required for the appearance of DMX3 also in later life.

Multifamily psychoeducation groups (MFPG) for families of children with bipolar disorder

Multi-family psychoeducation groups (MFPG) have been developed and tested for adults, but not for children with bipolar disorder (BPD). We present data from a pilot study of our manual-driven MFPG treatment for families of children with mood disorders and address two questions: Do families of children with BPD and families of children with major depressive disorder/dysthymic disorder (MDD/DD): 1) differ at treatment entry?; 2) benefit equally from intervention? A total of 35 children (n=16, BPD; n=19, MDD/DD) aged 8-11 years and their parents were randomized into immediate MFPG plus treatment as usual (TAU) or wait-list + TAU and assessed periodically. At baseline, there was a trend toward parents in BPD families being more knowledgeable about mood symptoms than parents in MDD/DD families (p < 0.04). Additionally at baseline, children with BPD evidenced greater mood severity historically and a trend toward more hospitalizations, day treatment, outpatient treatment, medication trials, and placement in special education classrooms than children with MDD/DD. Immediately following and 4 months post-treatment, both BPD and MDD/DD families described having gained knowledge, skills, support, and positive attitudes during treatment. MDD/DD families increased their knowledge of symptoms to the same level as BPD families. While BPD families enter treatment with more impaired children and more extensive treatment histories, both BPD and MDD/DD families benefit from intervention. The clinical issues concerning combining families of children with bipolar and depressive spectrum illnesses in groups are discussed. Clinical impressions suggest that such combinations are clinically feasible and potentially beneficial.

Characterization of children of bipolar parents by parent report CBCL

In past research the Child Behavior Checklist (CBCL) has differentiated among various diagnostic categories for children and adolescents. However, research has not been conducted on whether the CBCL differentiates among diagnostic categories for children at high risk for development of psychopathology. This study compares four diagnostic groups [bipolar disorder (BD), attention/deficit-hyperactivity disorder (ADHD), Depressed/Anxious and No Diagnosis] within a cohort of 58 children of bipolar parents to determine whether their CBCL scores will replicate the scores of children not at high risk for bipolar disorder. The cohort of children of bipolar parents received elevated scores on the CBCL scales in comparison with non-clinical populations. In addition, the CBCL distinguished between children of bipolar parents with and without clinical disorders. Finally the BD group differed from the ADHD group only on the Aggressive Behaviors, Withdrawn and Anxious/Depressed subscales of the CBCL. Therefore the CBCL did not discriminate between the BD and ADHD groups as it had in previous studies of children with BD and unspecified family history. It is possible that this discrepancy is due to a group of children of bipolar parents with ADHD who are currently prodromal for bipolar disorder and therefore received higher scores on the CBCL based on prodromal symptomatology. A longitudinal follow-up of this cohort is necessary to ascertain whether this is the case.

Comorbid bipolar disorder and panic disorder in families with a high prevalence of bipolar disorder.

Panic attacks are a common complication of affective disorder, although the etiologic relationship of panic and affective symptoms has not been determined. Evidence from a family study suggests that panic attacks and panic disorder may be related genetically to bipolar disorder. This study used diagnostic data from the NIMH Bipolar Disorder Genetics Initiative to assess in a separate, larger family set the familiality of panic combined with bipolar disorder. First-degree relatives (N=966) of probands with bipolar I disorder (N=192) and schizoaffective disorder, bipolar type, (N=11) were included in the study. All subjects were interviewed directly and were assigned best-estimate diagnoses for major affective and other psychiatric disorders. The risk of a family member being diagnosed with panic disorder if the proband with bipolar disorder had panic attacks or panic disorder was calculated with logistic regression analysis with generalized estimating equations that controlled for sex and affective disorder subdiagnosis. More than 90% of the probands and first-degree relatives with panic disorder also had an affective disorder diagnosis. Panic disorder was present in 17% of the relatives with recurrent major affective disorder and in 3% of the relatives without recurrent major affective disorder. Risk of panic disorder in relatives with bipolar disorder was increased significantly if the proband had panic attacks or panic disorder. Risk for panic disorder with familial bipolar disorder appears to be inherited. Inherited risk for panic disorder with bipolar disorder may indicate a shared genetic etiology for both disorders in some families. The patterns of bipolar disorder and panic disorder comorbidity observed in families imply a complex genetic etiology, which may be elucidated by using endophenotypes.

Abstracts for the IXth World Congress of Psychiatric Genetics, Saint Louis, Missouri

Abstracts for the IXth World Congress of Psychiatric Genetics, Saint Louis, Missouri

Schizophrenia and bipolar disorder: findings from studies of the Stanley Foundation Brain Collection

The Stanley Foundation Brain Collection contains a matched set of specimens from patients diagnosed with schizophrenia, bipolar disorder, non-psychotic depression and normal controls. Specimens have been shipped to investigators in more than 50 laboratories around the world. To date, results obtained from studies with this collection indicate that schizophrenia and bipolar disorder may both be characterized by abnormalities in frontal cortical interneurons, although different subpopulations of these neurons may be specifically affected in the two disorders. In samples from patients with familial bipolar disorder and major depression, there are alterations in glial density in cingulate cortex. Specific effects of antidepressant drugs on the transcription factor cAMP regulatory element binding protein and brain-derived neurotrophic factor have also been observed.

Prefrontal cortical-amygdalar metabolism in major depression.

Functional neuroimaging studies of the anatomical correlates of familial major depressive disorder (MDD) and bipolar disorder (BD) have identified abnormalities of resting blood flow (BF) and glucose metabolism in depression in the amygdala and the orbital and medial prefrontal cortical (PFC) areas that are extensively connected with the amygdala. The amygdala metabolism in MDD and BD is positively correlated with both depression severity and "stressed" plasma cortisol concentrations measured during scanning. During antidepressant drug treatment, the mean amygdala metabolism decreases in treatment responders, and the persistence of elevated amygdala metabolism during remission is associated with a high risk for the development of depressive relapse. The orbital C metabolism is also abnormally elevated during depression, but is negatively correlated with both depression severity and amygdala metabolism, suggesting that this structure may be activated as a compensatory mechanism to modulate amygdala activity or amygdala-driven emotional responses. The posterior orbital C and anterior cingulate C ventral to the genu of the corpus callosum (subgenual PFC) have more recently been shown in morphometric MRI and/or post mortem histopathological studies to have reduced grey matter volume and reduced glial cell numbers (with no equivalent loss of neurons) in familial MDD and BD. These data suggest a neural model in which dysfunction of limbic PFC structures impairs the modulation of the amygdala, leading to abnormal processing of emotional stimuli. Antidepressant drugs may compensate for this dysfunction by inhibiting pathological limbic activity.

Networks within the orbital and medial prefrontal cortex

The orbital and medial regions of the prefrontal cortex (OMPFC) can be divided into at least 22 architectonic areas, based on differences in staining with a number of methods and on differences in connections. The connections of these areas indicate that they can be divided into two interconnected groups or networks. The orbital network includes most of the areas on the orbital surface, and receives inputs from several sensory modalities that appear to be related to food or feeding. The medial network includes areas on the medial surface, and a few orbital areas. It provides output to visceromotor control areas in the hypothalamus and periaqueductal gray. Both networks have substantial interconnections with limbic structures, including the amygdala and hippocampal formation, suggesting that the OMPFC is involved in affective as well as sensory and visceromotor functions. This is strengthened by imaglng studies of mood disorders in humans, which indicate that areas within the OMPFC have abnormal activity (either increased or decreased) in patients with familial major depressive disorder and bipolar disorder.

Familial bipolar disorder: preliminary results from the Otago Familial Bipolar Genetic Study.

This paper outlines the methodologies used, and preliminary descriptive data collected, on a cohort of familial bipolar disorder (BPD) probands and first-degree relatives taking part in a descriptive and genetic study into familial BPD in New Zealand. Fifty-five bipolar probands and 67 first-degree relatives were interviewed using the modified Diagnostic Interview for Genetic Studies (DIGS) and Family Interview for Genetic Studies (FIGS). Data was also collated from other sources. Blood samples were taken for DNA genomic analysis. New Zealand families in which BPD segregates proved willing participants in this familial based genetic research. The methodologies used were acceptable. High rates of comorbidity were found in probands (27.3% met DSM-IV criteria for panic disorder/sub-threshold panic disorder; 12.7% for phobic disorder; 1.8% for obsessive-compulsive disorder; 9.1% for alcohol-related disorders and 7.3% for an eating disorder) and relatives (major depression 34.3%; panic disorder/sub-threshold panic disorder 12.0%; phobias 11.9% and alcohol-related disorders 11.9%). The polarity of index BPD illness was related to age of onset and frequency of comorbidity. Suicidal behaviour was common. Psychiatric genetic research in New Zealand families is highly feasible. Emerging trends in the familial transmission of BPD include high rates of comorbidity, illness patterns based on polarity of index episode and frequent suicidal behaviour. Such trends will be delineated further as numbers accrue, perhaps enabling identification of more homogenous phenotypic subgroups than currently produced by diagnostic schemes.

Glial reduction in the subgenual prefrontal cortex in mood disorders.

Mood disorders are among the most common neuropsychiatric illnesses, yet little is known about their neurobiology. Recent neuroimaging studies have found that the volume of the subgenual part of Brodmann's area 24 (sg24) is reduced in familial forms of major depressive disorder (MDD) and bipolar disorder (BD). In this histological study, we used unbiased stereological techniques to examine the cellular composition of area sg24 in two different sets of brains. There was no change in the number or size of neurons in area sg24 in mood disorders. In contrast, the numbers of glia were reduced markedly in both MDD and BD. The reduction in glial number was most prominent in subgroups of subjects with familial MDD (24%, P = 0.01) or BD (41%, P = 0.01). The glial reduction in subjects without a clear family history was lower in magnitude and not statistically significant. Consistent with neuroimaging findings, cortical volume was reduced in area sg24 in subjects with familial mood disorders. Schizophrenic brains studied as psychiatric controls had normal neuronal and glial numbers and cortical volume. Glial and neuronal numbers also were counted in area 3b of the somatosensory cortex in the same group of brains and were normal in all psychiatric groups. Glia affect several processes, including regulation of extracellular potassium, glucose storage and metabolism, and glutamate uptake, all of which are crucial for normal neuronal activity. We thus have identified a biological marker associated with familial mood disorders that may provide important clues regarding the pathogenesis of these common psychiatric conditions.

Panic disorder with familial bipolar disorder

If bipolar disorder is genetically heterogeneous, it may be possible to discern clinically heterogeneous familial subtypes based on differential risk for psychiatric comorbidity, for example panic disorder. We evaluated 528 members of 57 families ascertained for a genetic linkage study of bipolar disorder. Families were assorted according to the panic disorder diagnosis of the bipolar proband; the rates of panic and other disorders in relatives were compared. Eighty-eight percent of the 41 subjects with panic disorder had bipolar disorder. Panic disorder was diagnosed in 18% of family members with bipolar disorder. Ten of 57 bipolar probands had panic disorder. Their bipolar first-degree relatives had a significantly higher prevalence of panic disorder, bipolar II, cyclothymia, and dysthymia, but had lower prevalence of substance abuse than the relatives of the bipolar probands without panic disorder. These findings suggest the testable hypothesis that comorbid panic disorder is a marker of genetic heterogeneity in bipolar disorder.

Intérêt d'une seconde cure d'interféron a chez des patients atteints d'hépatite virale C

Schizophrenia and bipolar disorder share genetic liability, and some structural brain abnormalities are common to both conditions. First-degree relatives of patients with schizophrenia (FDRs-SZ) show similar brain abnormalities to patients, albeit with smaller effect sizes. Imaging findings in first-degree relatives of patients with bipolar disorder (FDRs-BD) have been inconsistent in the past, but recent studies report regionally greater volumes compared with control subjects.We performed a meta-analysis of global and subcortical brain measures of 6008 individuals (1228 FDRs-SZ, 852 FDRs-BD, 2246 control subjects, 1016 patients with schizophrenia, 666 patients with bipolar disorder) from 34 schizophrenia and/or bipolar disorder family cohorts with standardized methods. Analyses were repeated with a correction for intracranial volume (ICV) and for the presence of any psychopathology in the relatives and control subjects.FDRs-BD had significantly larger ICV (d = +0.16, q < .05 corrected), whereas FDRs-SZ showed smaller thalamic volumes than control subjects (d = −0.12, q < .05 corrected). ICV explained the enlargements in the brain measures in FDRs-BD. In FDRs-SZ, after correction for ICV, total brain, cortical gray matter, cerebral white matter, cerebellar gray and white matter, and thalamus volumes were significantly smaller; the cortex was thinner (d < −0.09, q < .05 corrected); and third ventricle was larger (d = +0.15, q < .05 corrected). The findings were not explained by psychopathology in the relatives or control subjects.Despite shared genetic liability, FDRs-SZ and FDRs-BD show a differential pattern of structural brain abnormalities, specifically a divergent effect in ICV. This may imply that the neurodevelopmental trajectories leading to brain anomalies in schizophrenia or bipolar disorder are distinct.

A possible vulnerability locus for bipolar affective disorder on chromosome 21q22.3.

In a preliminary genome scan of 47 bipolar disorder families, we detected in one family a lod score of 3.41 at the PFKL locus on chromosome 21q22.3. The lod score is robust to marker allele frequencies, phenocopy rates and age-dependent penetrance, and remains strongly positive with changes in affection status. Fourteen other markers in 21q22.3 were tested on this family, with largely positive lod scores. Five of the other 46 families also show positive, but modest lod scores with PFKL. When all 47 families are analysed together, there is little support for linkage to PFKL under homogeneity or heterogeneity using lod score analysis, but the model-free affected-pedigree-member method yields statistically significant results (p < 0.0003). Our results are consistent with the presence of a gene in 21q22.3 predisposing at least one family to bipolar disorder.

Population frequencies of tyrosine hydroxylase restriction fragment length polymorphisms in bipolar affective disorder

Linkage studies have demonstrated two distinct genetic forms of familial bipolar affective disorder with locations near chromosome 11~15 (Egeland et al. 1987) and chromosome Xq27 (Reich et al. 1969; Baron et al. 1987; Mendlewicz et al. 1987). What proportion of familial bipolar illness can be attributed to these two loci is unknown. Indeed, several families have been described in which linkage to these loci can be ruled out (~tera-Wadleigh et al. 1987; Hodgkinson et al. 1987). ley et al. 1987) provides the tools to investigate DNA polymorphisms that may be associated with this gene.