Patterns of maternal transmission in bipolar affective disorder.

The mode of inheritance of bipolar affective disorder (BPAD) appears complex, and non-Mendelian models of inheritance have been postulated. Two non-Mendelian phenomena, genomic imprinting and mitochondrial inheritance, may contribute to the complex inheritance pattern seen in BPAD. Both imprinting and mitochondrial inheritance share the feature of differential expression of the phenotype, depending on the parent of origin. In this study we tested the hypothesis of a parent-of-origin effect on the transmission of BPAD. We examined the frequency and risk of affective disorder among relatives in a sample of 31 families ascertained through treated probands with BPAD and selected for the presence of affected phenotypes in only one parental lineage. Three specific comparisons were performed: (1) the observed frequency of transmitting mothers versus transmitting fathers; (2) the observed frequency and lifetime risk of BPAD among the maternal versus the paternal relatives of probands; and (3) the observed frequency and lifetime risk of BPAD for the offspring of affected mothers compared with the offspring of affected fathers. We observed a higher than expected frequency of affected mothers (P < .04), a 2.3-2.8-fold increased risk of illness for maternal relatives (P < .006), and a 1.3- 2.5-fold increased risk of illness for the offspring of affected mothers (P < .017).In seven enlarged pedigrees, fathers repeatedly failed to transmit the affected phenotype to daughters or sons. Taken together, these findings indicate a maternal effect in the transmission of BPAD susceptibility and suggest that molecular studies of mtDNA and imprinted DNA are warranted in patients with BPAD.     

Mitochondrial genetic analyses suggest selection against maternal lineages in bipolar affective disorder.

Previous reports of preferential transmission of bipolar affective disorder (BP) from the maternal versus the paternal lines in families suggested that this disorder may be caused by mitochondrial DNA mutations. We have sequenced the mitochondrial genome in 25 BP patients with family histories of psychiatric disorder that suggest matrilineal inheritance. No polymorphism identified more than once in this sequencing showed any significant association with BP in association studies using 94 cases and 94 controls. To determine whether our BP sample showed evidence of selection against the maternal lineage, we determined genetic distances between all possible pairwise comparisons within the BP and control groups, based on multilocus mitochondrial polymorphism haplotypes. These analyses revealed fewer closely related haplotypes in the BP group than in the matched control group, suggesting selection against maternal lineages in this disease. Such selection is compatible with recurrent mitochondrial mutations, which are associated with slightly decreased fitness. Although such mismatch distribution comparisons have been used previously for analyses of population histories, this is, as far as we are aware, the first report of this method being used to study disease.     

A susceptibility locus for bipolar affective disorder on chromosome 4q35.

Bipolar affective disorder (BAD) affects approximately 1% of the population and shows strong heritability. To identify potential BAD susceptibility loci, we undertook a 15-cM genome screen, using 214 microsatellite markers on the 35 most informative individuals of a large, statistically powerful pedigree. Data were analyzed by parametric two-point linkage methods under several diagnostic models. LOD scores >1.00 were obtained for 21 markers, with four of these >2.00 for at least one model. The remaining 52 individuals in the family were genotyped with these four markers, and LOD scores remained positive for three markers. A more intensive screen was undertaken in these regions, with the most positive results being obtained for chromosome 4q35. Using a dominant model of inheritance with 90% maximum age-specific penetrance and including bipolar I, II, schizoaffective/mania, and unipolar individuals as affected, we obtained a maximum two-point LOD score of 2.20 (theta = .15) at D4S1652 and a maximum three-point LOD score of 3.19 between D4S408 and D4S2924. Nonparametric analyses further supported the presence of a locus on chromosome 4q35. A maximum score of 2.62 (P=.01) was obtained between D4S1652 and D4S171 by use of the GENEHUNTER program, and a maximum score of 3.57 (P=.0002) was obtained at D4S2924 using the affected pedigree member method. Analysis of a further 10 pedigrees suggests the presence of this locus in at least one additional family, indicating a possible predisposing locus and not a pedigree-specific mutation. Our results suggest the presence of a novel BAD susceptibility locus on chromosome 4q35.     

Abnormal signal transduction: a hypothetical model for bipolar affective disorder

The molecular basis of bipolar affective disorder is poorly understood at this time. The episodic nature of the condition in which relatively euthymic periods of variable duration separate periods of mania and depression, and the specificity of lithium therapy suggests that a molecular target of the illness may be a system that bidirectionally influences neurotransmission and is affected by lithium. Signal transduction pathways, which are important mediators of neurotransmitter generated signals, may represent such a system because they: 1) generate second messenger molecules that stimulate neurotransmission and also mediate negative feedback mechanisms, and 2) appear to be a direct target of lithium's action on cells. In this paper, we present a model in which abnormal regulation of signal transduction could lead to the episodic accumulation of biologically active transducers or second messengers. These alterations may result in prolonged effector stimulation which may underlie mania, followed by excessive receptor desensitization, which may result in depression. Using our model we suggest a plausible hypothesis that can explain the clinical spectrum of the disorder and the therapeutic action of lithium.     

Genetic linkage analysis of bipolar affective disorder in an Old Order Amish pedigree

Summary We have used genetic linkage analysis in an effort to identify a gene responsible for bipolar affective disorder (BAD) in an Old Order Amish pedigree. The initial study of this pedigree showed strong evidence for linkage of the chromosome 11p15 markers HRAS1 and the insulin gene (INS) to BAD, whereas a second report found no evidence for linkage. We have independently determined the INS and HRAS1 genotypes from 81 individuals in this pedigree. A polymerase chain reaction (PCR) assay was used to score INS alleles that are difficult to distinguish from one another by conventional agarose gel electrophoresis. In addition, we used four separate diagnostic models to score individuals with psychiatric illness as either affected or unaffected. No evidence of significant linkage between BAD and the markers was found with either two-point or multipoint analysis regardless of which diagnostic model was used. However, exclusion of the region of chromosome 11 between INS and RAS1 as a possible location for the BAD gene in this family depended on the diagnostic model. Further genetic linkage studies with additional DNA markers that span the genome are necessary to determine the chromosomal location of the BAD gene in this family.     

Schizophrenia and bipolar affective disorder: perspectives for the development of therapeutics

Schizophrenia and bipolar disorder remain two of the most severe and difficult to treat psychotic disorders hampered by our poor understanding of their pathologies. The development of typical antipsychotic drugs opened an avenue of investigation through the dopamine D2 receptor in schizophrenia. With the reintroduction of the atypical antipsychotic clozapine came the development of a new generation of atypical agents and hypotheses challenging the centrality of this receptor in explaining antipsychotic effects. Evaluation of these competing theories does not provide sufficient evidence to displace the importance of the dopamine D2 receptor in antipsychotic efficacy, but does raise limitations of it as an explanatory hypothesis. Further, the treatment of other symptom domains in schizophrenia remains relatively neglected and open for the development of novel therapies. Similar to schizophrenia, bipolar disorder presents a diversity of clinical states but unlike schizophrenia, its mainstay of treatment, lithium, has not had a clear receptor target impeding understanding of the disorder's pathology and treatment. This has pushed investigation into other domains emphasising a number of intracellular signalling pathways and glial-neuronal interactions. The heavy genetic loading of bipolar disorder has allowed linkage analyses to identify a number of putative regions, however, the diversity of phenotypes complicates such studies. Polymorphisms of candidate genes have yielded potential leads such as dopamine beta hydroxylase in mood disorder and the serotonin transporter for treatment response. It is anticipated that combiningthe above approaches may hold promise for the development of more effective treatments.     

Altered cAMP-dependent protein kinase subunit immunolabeling in post-mortem brain from patients with bipolar affective disorder

Previous findings of reduced [3H]cAMP binding and increased activities of cAMP-dependent protein kinase (PKA) in discrete post-mortem brain regions from patients with bipolar affective disorder (BD) suggest that PKA, the major downstream target of cAMP, is also affected in this illness. As prolonged elevation of intracellular cAMP levels can modify PKA regulatory (R) and catalytic (C) subunit levels, we sought to determine whether these PKA abnormalities are related to changes in the abundance of PKA subunits in BD brain. Using immunoblotting techniques along with PKA subunit isoform-specific polyclonal antisera, levels of PKA RIalpha, RIbeta, RIIalpha, RIIbeta and Calpha subunits were measured in cytosolic and particulate fractions of temporal, frontal and parietal cortices of post-mortem brain from BD patients and matched, non-neurological, non-psychiatric controls. Immunoreactive levels of cytosolic Calpha in temporal and frontal cortices, as well as that of cytosolic RIIbeta in temporal cortex, were significantly higher in the BD compared with the matched control brains. These changes were independent of age, post-mortem interval or pH and unrelated to ante-mortem lithium treatment or suicide. These findings strengthen further the notion that the cAMP/PKA signaling system is up-regulated in discrete cerebral cortical regions in BD.     

Genetic variation of the 5-HT2A receptor gene and bipolar affective disorder

Abnormalities of the serotonergic system have classically been associated with the origin of affective disorders through the biochemical action of therapeutic agents and their role in affective and perceptual states. In the present study, we hypothesized that genetic variation in the 5-hydroxytryptamine (serotonin) type 2A (5-HT_2A ) receptor gene (HTR2A) might have an effect on the aetiology of bipolar affective disorder. Four different polymorphisms in the HTR2A gene were studied in 88 patients with bipolar affective disorder and 113 healthy controls, all of Spanish origin. No significant association was observed between any of the four polymorphisms at the HTR2A locus, whether tested individually or as haplotypes, and bipolar affective disorder. The lack of association suggests that HTR2A is not a major risk factor for bipolar affective disorder. Received: 4 December 1996 / Accepted: 15 April 1997     

Diagnosis of bipolar disorders: focus on bipolar disorder I and bipolar disorder II

Bipolar disorders are currently divided into 4 entities: bipolar I, bipolar II, cyclothymic disorder, and bipolar disorder not otherwise specified, as described in the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV). These subtypes of bipolar disorders cover a spectrum of severities, frequencies, and durations of manic and depressive symptoms. The differential diagnosis among these and with regard to other disorders with similar symptom features remains the foundation for treatment of bipolar disorders. It is clear that much diversity exists within these major subtypes, such that designations like "rapid cycling" and "bipolar III" are being put forward and probed for clinical relevance. Some of the concerns and advantages of including these less-established manifestations of bipolar disorders in our diagnostic thinking are discussed here, and the utility and drawbacks of our current diagnostic protocols are considered.     

Serological markers in unipolar and bipolar affective disorders

ABO blood groups and haptoglobin types have been studied with special reference to their association with unipolar and bipolar affective disorders. The associations of serogenetic markers show statistically significant differences between unipolars and controls, bipolars and controls, and unipolars and bipolars. The results are largely in agreement with those reported in previous studies.     

A comprehensive linkage analysis of chromosome 21q22 supports prior evidence for a putative bipolar affective disorder locus.

Previously, we demonstrated evidence of linkage to bipolar affective disorder (BP) in a single large, multigenerational family with a LOD score of 3.41 at the PFKL locus on chromosome 21q22.3. Additional families showed little support for linkage to PFKL under homogeneity or heterogeneity, in that study. We have expanded on that analysis, with 31 microsatellite markers at an average marker spacing of </=2 cM, in the largest multigenerational BP pedigree series reported to date. A two-point heterogeneity (alpha=0.5) LOD score of 3.35 (P<.000156) was found at the D21S1260 locus, 5 cM proximal to PFKL. Polylocus analysis with a cluster of three neighboring markers was consistent with these results (PL-HetLOD = 3.25). In the design of this study, 373 individuals from 40 families (from a total set of 1,508 individuals in 57 families) were chosen, as a cost-effective approach to genotyping this large sample set. Linkage analyses were performed with an "affecteds-only" method. As such, our results are based solely on genetic information from affected individuals, without assumptions about the disease-locus genotypes of the unaffecteds. Furthermore, for ease of comparison, this study was performed with the same approach as a 10-cM genome scan for BP loci, the results of which will be reported elsewhere.     

Chronic somatic comorbidity and excess mortality due to natural causes in persons with schizophrenia or bipolar affective disorder

Background

Suicide and death by accidents in persons with schizophrenia and bipolar disorder are common, but excess mortality from natural death accounts for even more years of life lost. The impact of somatic comorbidity, however, often is not duly considered in analyses and explanations of excess mortality in patients with psychotic disorders.

Objective/Methods

This study investigates and evaluates the impact of 19 severe chronic diseases on excess mortality due to diseases and medical conditions (natural death) in individuals with psychotic disorders compared with the general population using a population-based cohort study in Denmark. Incidence/mortality rate ratios of admission/mortality were calculated using survival analysis.

Results

Cohort members with psychotic disorders had higher incidence rates of hospital contacts for almost all of the 19 disorders than the general population. The mortality rate ratio (MRR) of natural death was 7.10 (95% CI 6.45, 7.81) for schizophrenic men, decreasing to 4.64 (95% CI 4.21, 5.10) after adjustment for the somatic disorders. The same pattern existed in women and in both genders with bipolar disorder. Highest MRRs were observed for psychotic patients without hospital admissions with the investigated somatic disorders.

Conclusion

Chronic somatic diseases accounted for half of the excess mortality in patients with schizophrenia or bipolar disorder. Chronic disorders investigated in this paper seem to be under-treated or under-detected among such patients.