Environmental factors, life events, and trauma in the course of bipolar disorder

The etiology and clinical course of bipolar disorder are considered to be determined by genetic and environmental factors. Although the kindling hypothesis emphasizes the impact of environmental factors on initial onset, their connection to the outcome and clinical course have been poorly established. Hence, there have been numerous research efforts to investigate the impact of environmental factors on the clinical course of illness. Our aim is to outline recent research on the impact of environmental determinants on the clinical course of bipolar disorder. We carried out a computer-aided search to find publications on an association between environmental factors, life events, and the clinical course of bipolar disorder. Publications in the reference lists of suitable papers have also been taken into consideration. We performed a narrative overview on all eligible publications. The available body of data supports an association between environmental factors and the clinical course of bipolar disorder. These factors comprise prenatal, early-life, and entire lifespan aspects. Given varying sample sizes and several methodological limitations, the reported quality and extent of the association between environmental factors and the clinical course of bipolar disorder should be interpreted with utmost caution. Systematic longitudinal long-term follow-up trials are needed to obtain a clearer and more robust picture

Psychopathological Course Typology in Schizophrenia Spectrum Disorders: A Heuristic Approach in a Sample of 100 Patients

Background: Despite several previous attempts at subtyping schizophrenia, a typology that reflects neurobiological knowledge and reliably predicts course and outcome is lacking. We applied the system-specific concept of the Bern Psychopathology Scale (BPS) to generate a course typology based on three domains: language, affectivity, and motor behaviour. Sampling and Methods: A cohort of 100 patients with schizophrenia or schizoaffective disorders according to DSM-IV criteria underwent psychopathological assessment, and all their available medical records were retrospectively analysed on the basis of the BPS. Results: Overall, 39% of the patients showed dominant abnormalities in only one domain, 37% in two domains, and 24% in all three domains. The motor domain was affected in the majority of patients (76%), followed by affectivity (63%) and language (46%). Eighty-six percent of patients showed a bipolar course pattern in at least one domain. Conclusions: In a retrospective analysis of 100 patient records we described system-specific course patterns of schizophrenia by using a neurobiologically informed psychopathological assessment. The results showed a surprisingly high proportion of bipolar courses and a pattern of pure and mixed subtypes, which speaks for an overlap of domains with regards to psychopathological symptoms. A limitation of this heuristic and retrospective approach is that it was largely based on clinical judgement. Prospective studies with more rigorous threshold definitions are needed to clarify the neurobiological and clinical implications of the proposed reorganization of psychotic disorders. (C) 2016 S. Karger AG, Base

Genomic and neuroimaging approaches to bipolar disorder

BACKGROUND: To date, besides genome-wide association studies, a variety of other genetic analyses (e.g. polygenic risk scores, whole-exome sequencing and whole-genome sequencing) have been conducted, and a large amount of data has been gathered for investigating the involvement of common, rare and very rare types of DNA sequence variants in bipolar disorder. Also, non-invasive neuroimaging methods can be used to quantify changes in brain structure and function in patients with bipolar disorder. AIMS: To provide a comprehensive assessment of genetic findings associated with bipolar disorder, based on the evaluation of different genomic approaches and neuroimaging studies. METHOD: We conducted a PubMed search of all relevant literatures from the beginning to the present, by querying related search strings. RESULTS: ANK3, CACNA1C, SYNE1, ODZ4 and TRANK1 are five genes that have been replicated as key gene candidates in bipolar disorder pathophysiology, through the investigated studies. The percentage of phenotypic variance explained by the identified variants is small (approximately 4.7%). Bipolar disorder polygenic risk scores are associated with other psychiatric phenotypes. The ENIGMA-BD studies show a replicable pattern of lower cortical thickness, altered white matter integrity and smaller subcortical volumes in bipolar disorder. CONCLUSIONS: The low amount of explained phenotypic variance highlights the need for further large-scale investigations, especially among non-European populations, to achieve a more complete understanding of the genetic architecture of bipolar disorder and the missing heritability. Combining neuroimaging data with genetic data in large-scale studies might help researchers acquire a better knowledge of the engaged brain regions in bipolar disorder

The Genetics of Response to and Side Effects of Lithium Treatment in Bipolar Disorder: Future Research Perspectives

Although the mood stabilizer lithium is a first-line treatment in bipolar disorder, a substantial number of patients do not benefit from it and experience side effects. No clinical tool is available for predicting lithium response or the occurrence of side effects in everyday clinical practice. Multiple genetic research efforts have been performed in this field because lithium response and side effects are considered to be multifactorial endophenotypes. Available results from linkage and segregation, candidate-gene, and genome-wide association studies indicate a role of genetic factors in determining response and side effects. For example, candidate-gene studies often report GSK3β, brain-derived neurotrophic factor, and SLC6A4 as being involved in lithium response, and the latest genome-wide association study found a genome-wide significant association of treatment response with a locus on chromosome 21 coding for two long non-coding RNAs. Although research results are promising, they are limited mainly by a lack of replicability and, despite the collaboration of consortia, insufficient sample sizes. The need for larger sample sizes and “multi-omics” approaches is apparent, and such approaches are crucial for choosing the best treatment options for patients with bipolar disorder. In this article, we delineate the mechanisms of action of lithium and summarize the results of genetic research on lithium response and side effects

Symptom profiles and illness course among Anabaptist and Non-Anabaptist adults with major mood disorders

Background: Anabaptists comprise large and growing Amish and Mennonite populations with a unique genetic heritage and cultural background. Little is known about the symptoms and course of major mood disorders in Anabaptists. Even less is known about the impact of potential moderators on symptom severity and course. Methods: A sample of Amish and Mennonite participants with bipolar, recurrent unipolar, or schizoaffective bipolar disorder (n = 155) were systematically evaluated with a well-validated instrument. Cases were compared with non-Anabaptist participants (n = 155) matched for age, sex, and psychiatric diagnosis and evaluated by the same methods. Results: Despite substantial cultural differences, the profile of manic and depressive symptoms during illness episodes did not significantly differ between the two groups. Alcohol use disorder (AUD) was significantly less frequent among Anabaptists, and was associated with more major depressive episodes and more hospitalizations for major depression in Anabaptist, but not non-Anabaptist participants. Lifetime history of head injury showed a trend toward association with more episodes of major depression in both Anabaptist and non-Anabaptist groups that did not withstand multiple test correction. Conclusions: The presentation of a highly heritable psychiatric illness such as bipolar disorder does not differ in cases drawn from genetically unique Anabaptist populations. However, alcohol comorbidity, head injury, and their effects on illness course suggest some differences that deserve further investigation

What Should a Psychiatrist Know About Genetics? Review and Recommendations From the Residency Education Committee of the International Society of Psychiatric Genetics.

The International Society of Psychiatric Genetics (ISPG) created a Residency Education Committee with the purpose of identifying key genetic knowledge that should be taught in psychiatric training programs. Thirteen committee members were appointed by the ISPG Board of Directors, based on varied training, expertise, gender, and national origin. The Committee has met quarterly for the past 2 years, with periodic reports to the Board and to the members of the Society. The information summarized includes the existing literature in the field of psychiatric genetics and the output of ongoing large genomics consortia. An outline of clinically relevant areas of genetic knowledge was developed, circulated, and approved. This document was expanded and annotated with appropriate references, and the manuscript was developed. Specific information regarding the contribution of common and rare genetic variants to major psychiatric disorders and treatment response is now available. Current challenges include the following: (1) Genetic testing is recommended in the evaluation of autism and intellectual disability, but its use is limited in current clinical practice. (2) Commercial pharmacogenomic testing is widely available, but its utility has not yet been clearly established. (3) Other methods, such as whole exome and whole genome sequencing, will soon be clinically applicable. The need for informed genetic counseling in psychiatry is greater than ever before, knowledge in the field is rapidly growing, and genetic education should become an integral part of psychiatric training

Prognostic relevance of mitral and tricuspid regurgitation after transcatheter aortic valve implantation: Impact of follow-up time point for decision-making

Background: In patients with aortic stenosis treated by transcatheter aortic valve implantation (TAVI), mitral and tricuspid regurgitation (MR and TR) at baseline and after TAVI are likely to be of prognostic relevance, and questions such as whether and when treatment further improves prognosis in these patients arise. Aims: Against that background, the purpose of this study was to analyze a variety of clinical characteristics including MR and TR with respect to their potential value as predictors of 2-year mortality after TAVI. Methods: A cohort of 445 typical TAVI patients was available for the study and clinical characteristics were evaluated baseline, 6 to 8 weeks as well as 6 months after TAVI. Results: In 39% of the patients relevant (moderate or severe) MR and in 32% of the patients relevant (moderate or severe) TR could be detected at baseline. The rates were 27% for MR ( p  = 0.001, compared to baseline) and 35% for TR ( p  = n.s., compared to baseline) at the 6- to 8-week follow-up. After 6 months, relevant MR was observable in 28% ( p  = 0.036, compared to baseline) and relevant TR in 34% ( p  = n.s., compared to baseline) of the patients. As predictors of 2-year mortality, a multivariate analysis identified the following parameters for the different time points: sex, age, AS entity, atrial fibrillation, renal function, relevant TR, systolic pulmonary artery pressure (PAPsys), and 6-min walk distance at baseline; clinical frailty scale and PAPsys 6–8 weeks after TAVI and BNP and relevant MR 6 months after TAVI. There was a significantly worse 2-year survival in patients with relevant TR at baseline (68.4% vs. 82.6%, p  < 0.001; whole population, n  = 445) and in patients with relevant MR at 6 months (87.9% vs. 95.2%, p  = 0.042; landmark analysis: n  = 235). Conclusion: This real-life study demonstrated the prognostic relevance of repeated evaluation of MR and TR before and after TAVI. Choosing the right time point for treatment is a remaining clinical challenge, which should be further addressed in randomized trials

COMT val158met Polymorphism and Neural Pain Processing

A functional polymorphism (val158met) of the gene coding for Catechol-O-methyltransferase (COM) has been demonstrated to be related to processing of emotional stimuli. Also, this polymorphism has been found to be associated with pain regulation in healthy subjects. Therefore, we investigated a possible influence of this polymorphism on pain processing in healthy persons as well as in subjects with markedly reduced pain sensitivity in the context of Borderline Personality Disorder (BPD). Fifty females (25 patients with BPD and 25 healthy control participants) were included in this study. Genotype had a significant – though moderate - effect on pain sensitivity, but only in healthies. The number of val alleles was correlated with the BOLD response in several pain-processing brain regions, including dorsolateral prefrontal cortex, posterior parietal cortex, lateral globus pallidus, anterior and posterior insula. Within the subgroup of healthy participants, the number of val alleles was positively correlated with the BOLD response in posterior parietal, posterior cingulate, and dorsolateral prefrontal cortex. BPD patients revealed a positive correlation between the number of val alleles and BOLD signal in anterior and posterior insula. Thus, our data show that the val158met polymorphism in the COMT gene contributes significantly to inter-individual differences in neural pain processing: in healthy people, this polymorphism was more related to cognitive aspects of pain processing, whereas BPD patients with reduced pain sensitivity showed an association with activity in brain regions related to affective pain processing

Segment-Wise Genome-Wide Association Analysis Identifies a Candidate Region Associated with Schizophrenia in Three Independent Samples

Recent studies suggest that variation in complex disorders (e.g., schizophrenia) is explained by a large number of genetic variants with small effect size (Odds Ratio∼1.05–1.1). The statistical power to detect these genetic variants in Genome Wide Association (GWA) studies with large numbers of cases and controls (∼15,000) is still low. As it will be difficult to further increase sample size, we decided to explore an alternative method for analyzing GWA data in a study of schizophrenia, dramatically reducing the number of statistical tests. The underlying hypothesis was that at least some of the genetic variants related to a common outcome are collocated in segments of chromosomes at a wider scale than single genes. Our approach was therefore to study the association between relatively large segments of DNA and disease status. An association test was performed for each SNP and the number of nominally significant tests in a segment was counted. We then performed a permutation-based binomial test to determine whether this region contained significantly more nominally significant SNPs than expected under the null hypothesis of no association, taking linkage into account. Genome Wide Association data of three independent schizophrenia case/control cohorts with European ancestry (Dutch, German, and US) using segments of DNA with variable length (2 to 32 Mbp) was analyzed. Using this approach we identified a region at chromosome 5q23.3-q31.3 (128–160 Mbp) that was significantly enriched with nominally associated SNPs in three independent case-control samples. We conclude that considering relatively wide segments of chromosomes may reveal reliable relationships between the genome and schizophrenia, suggesting novel methodological possibilities as well as raising theoretical questions