| 31. |
- Herrera-Rivero, Marisol, et al.
(author)
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Exploring the genetics of lithium response in bipolar disorders.
- 2023
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In: Research square.
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Other publication (other academic/artistic)abstract
- Lithium (Li) remains the treatment of choice for bipolar disorders (BP). Its mood-stabilizing effects help reduce the long-term burden of mania, depression and suicide risk in patients with BP. It also has been shown to have beneficial effects on disease-associated conditions, including sleep and cardiovascular disorders. However, the individual responses to Li treatment vary within and between diagnostic subtypes of BP (e.g. BP-I and BP-II) according to the clinical presentation. Moreover, long-term Li treatment has been linked to adverse side-effects that are a cause of concern and non-adherence, including the risk of developing chronic medical conditions such as thyroid and renal disease. In recent years, studies by the Consortium on Lithium Genetics (ConLiGen) have uncovered a number of genetic factors that contribute to the variability in Li treatment response in patients with BP. Here, we leveraged the ConLiGen cohort (N=2,064) to investigate the genetic basis of Li effects in BP. For this, we studied how Li response and linked genes associate with the psychiatric symptoms and polygenic load for medical comorbidities, placing particular emphasis on identifying differences between BP-I and BP-II.We found that clinical response to Li treatment, measured with the Alda scale, was associated with a diminished burden of mania, depression, substance and alcohol abuse, psychosis and suicidal ideation in patients with BP-I and, in patients with BP-II, of depression only. Our genetic analyses showed that a stronger clinical response to Li was modestly related to lower polygenic load for diabetes and hypertension in BP-I but not BP-II. Moreover, our results suggested that a number of genes that have been previously linked to Li response variability in BP differentially relate to the psychiatric symptomatology, particularly to the numbers of manic and depressive episodes, and to the polygenic load for comorbid conditions, including diabetes, hypertension and hypothyroidism.Taken together, our findings suggest that the effects of Li on symptomatology and comorbidity in BP are partially modulated by common genetic factors, with differential effects between BP-I and BP-II.
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| 32. |
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| 33. |
- Hou, Liping, et al.
(author)
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Genome-wide association study of 40,000 individuals identifies two novel loci associated with bipolar disorder.
- 2016
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In: Human molecular genetics. - : Oxford University Press (OUP). - 1460-2083 .- 0964-6906. ; 25:15, s. 3383-94
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Journal article (peer-reviewed)abstract
- Bipolar disorder (BD) is a genetically complex mental illness characterized by severe oscillations of mood and behavior. Genome-wide association studies (GWAS) have identified several risk loci that together account for a small portion of the heritability. To identify additional risk loci, we performed a two-stage meta-analysis of >9 million genetic variants in 9,784 bipolar disorder patients and 30,471 controls, the largest GWAS of BD to date. In this study, to increase power we used ∼2,000 lithium-treated cases with a long-term diagnosis of BD from the Consortium on Lithium Genetics, excess controls, and analytic methods optimized for markers on the X-chromosome. In addition to four known loci, results revealed genome-wide significant associations at two novel loci: an intergenic region on 9p21.3 (rs12553324, p=5.87×10(-9); odds ratio=1.12) and markers within ERBB2 (rs2517959, p=4.53×10(-9); odds ratio=1.13). No significant X-chromosome associations were detected and X-linked markers explained very little BD heritability. The results add to a growing list of common autosomal variants involved in BD and illustrate the power of comparing well-characterized cases to an excess of controls in GWAS.
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| 34. |
- Kalman, Janos L, et al.
(author)
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Investigating polygenic burden in age at disease onset in bipolar disorder: Findings from an international multicentric study.
- 2019
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In: Bipolar disorders. - : Wiley. - 1399-5618 .- 1398-5647. ; 21:1, s. 68-75
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Journal article (peer-reviewed)abstract
- Bipolar disorder (BD) with early disease onset is associated with an unfavorable clinical outcome and constitutes a clinically and biologically homogenous subgroup within the heterogeneous BD spectrum. Previous studies have found an accumulation of early age at onset (AAO) in BD families and have therefore hypothesized that there is a larger genetic contribution to the early-onset cases than to late onset BD. To investigate the genetic background of this subphenotype, we evaluated whether an increased polygenic burden of BD- and schizophrenia (SCZ)-associated risk variants is associated with an earlier AAO in BD patients.A total of 1995 BD type 1 patients from the Consortium of Lithium Genetics (ConLiGen), PsyCourse and Bonn-Mannheim samples were genotyped and their BD and SCZ polygenic risk scores (PRSs) were calculated using the summary statistics of the Psychiatric Genomics Consortium as a training data set. AAO was either separated into onset groups of clinical interest (childhood and adolescence [≤18years] vs adulthood [>18years]) or considered as a continuous measure. The associations between BD- and SCZ-PRSs and AAO were evaluated with regression models.BD- and SCZ-PRSs were not significantly associated with age at disease onset. Results remained the same when analyses were stratified by site of recruitment.The current study is the largest conducted so far to investigate the association between the cumulative BD and SCZ polygenic risk and AAO in BD patients. The reported negative results suggest that such a polygenic influence, if there is any, is not large, and highlight the importance of conducting further, larger scale studies to obtain more information on the genetic architecture of this clinically relevant phenotype.
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| 35. |
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| 36. |
- Matosin, N, et al.
(author)
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Associations of psychiatric disease and ageing with FKBP5 expression converge on superficial layer neurons of the neocortex
- 2023
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In: Acta neuropathologica. - : Springer Science and Business Media LLC. - 1432-0533 .- 0001-6322. ; 145:4, s. 439-459
-
Journal article (peer-reviewed)abstract
- Identification and characterisation of novel targets for treatment is a priority in the field of psychiatry. FKBP5 is a gene with decades of evidence suggesting its pathogenic role in a subset of psychiatric patients, with potential to be leveraged as a therapeutic target for these individuals. While it is widely reported that FKBP5/FKBP51 mRNA/protein (FKBP5/1) expression is impacted by psychiatric disease state, risk genotype and age, it is not known in which cell types and sub-anatomical areas of the human brain this occurs. This knowledge is critical to propel FKBP5/1-targeted treatment development. Here, we performed an extensive, large-scale postmortem study (n = 1024) of FKBP5/1, examining neocortical areas (BA9, BA11 and ventral BA24/BA24a) derived from subjects that lived with schizophrenia, major depression or bipolar disorder. With an extensive battery of RNA (bulk RNA sequencing, single-nucleus RNA sequencing, microarray, qPCR, RNAscope) and protein (immunoblot, immunohistochemistry) analysis approaches, we thoroughly investigated the effects of disease state, ageing and genotype on cortical FKBP5/1 expression including in a cell type-specific manner. We identified consistently heightened FKBP5/1 levels in psychopathology and with age, but not genotype, with these effects strongest in schizophrenia. Using single-nucleus RNA sequencing (snRNAseq; BA9 and BA11) and targeted histology (BA9, BA24a), we established that these disease and ageing effects on FKBP5/1 expression were most pronounced in excitatory superficial layer neurons of the neocortex, and this effect appeared to be consistent in both the granular and agranular areas examined. We then found that this increase in FKBP5 levels may impact on synaptic plasticity, as FKBP5 gex levels strongly and inversely correlated with dendritic mushroom spine density and brain-derived neurotrophic factor (BDNF) levels in superficial layer neurons in BA11. These findings pinpoint a novel cellular and molecular mechanism that has potential to open a new avenue of FKBP51 drug development to treat cognitive symptoms in psychiatric disorders.
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| 37. |
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| 38. |
- Mayer, S, et al.
(author)
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European Psychiatric Association (EPA) guidance on post-graduate psychiatric training in Europe
- 2014
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In: European psychiatry : the journal of the Association of European Psychiatrists. - : Cambridge University Press (CUP). - 1778-3585. ; 29:2, s. 101-106
-
Journal article (peer-reviewed)abstract
- The European Union Free Movement Directive gives professionals the opportunity to work and live within the European Union, but does not give specific requirements regarding how the specialists in medicine have to be trained, with the exception of a required minimum of 4 years of education. Efforts have been undertaken to harmonize post-graduate training in psychiatry in Europe since the Treaty of Rome 1957, with the founding of the European Union of Medical Specialists (UEMS) and establishment of a charter outlining how psychiatrists should be trained. However, the different curricula for post-graduate training were only compared by surveys, never through a systematic review of the official national requirements. The published survey data still shows great differences between European countries and unlike other UEMS Boards, the Board of Psychiatry did not introduce a certification for specialists willing to practice in a foreign country within Europe. Such a European certification could help to keep a high qualification level for post-graduate training in psychiatry all over Europe. Moreover, it would make it easier for employers to assess the educational level of European psychiatrists applying for a job in their field.
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| 39. |
- Ou, Anna H., et al.
(author)
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Lithium response in bipolar disorder is associated with focal adhesion and PI3K-Akt networks: a multi-omics replication study
- 2024
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In: TRANSLATIONAL PSYCHIATRY. - 2158-3188. ; 14:1
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Journal article (peer-reviewed)abstract
- Lithium is the gold standard treatment for bipolar disorder (BD). However, its mechanism of action is incompletely understood, and prediction of treatment outcomes is limited. In our previous multi-omics study of the Pharmacogenomics of Bipolar Disorder (PGBD) sample combining transcriptomic and genomic data, we found that focal adhesion, the extracellular matrix (ECM), and PI3K-Akt signaling networks were associated with response to lithium. In this study, we replicated the results of our previous study using network propagation methods in a genome-wide association study of an independent sample of 2039 patients from the International Consortium on Lithium Genetics (ConLiGen) study. We identified functional enrichment in focal adhesion and PI3K-Akt pathways, but we did not find an association with the ECM pathway. Our results suggest that deficits in the neuronal growth cone and PI3K-Akt signaling, but not in ECM proteins, may influence response to lithium in BD.
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| 40. |
- Stubbs, B, et al.
(author)
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EPA guidance on physical activity as a treatment for severe mental illness: a meta-review of the evidence and Position Statement from the European Psychiatric Association (EPA), supported by the International Organization of Physical Therapists in Mental Health (IOPTMH)
- 2018
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In: European psychiatry : the journal of the Association of European Psychiatrists. - : Cambridge University Press (CUP). - 1778-3585. ; 54, s. 124-144
-
Journal article (peer-reviewed)abstract
- Physical activity (PA) may be therapeutic for people with severe mental illness (SMI) who generally have low PA and experience numerous life style-related medical complications. We conducted a meta-review of PA interventions and their impact on health outcomes for people with SMI, including schizophrenia-spectrum disorders, major depressive disorder (MDD) and bipolar disorder. We searched major electronic databases until January 2018 for systematic reviews with/without meta-analysis that investigated PA for any SMI. We rated the quality of studies with the AMSTAR tool, grading the quality of evidence, and identifying gaps, future research needs and clinical practice recommendations. For MDD, consistent evidence indicated that PA can improve depressive symptoms versus control conditions, with effects comparable to those of antidepressants and psychotherapy. PA can also improve cardiorespiratory fitness and quality of life in people with MDD, although the impact on physical health outcomes was limited. There were no differences in adverse events versus control conditions. For MDD, larger effect sizes were seen when PA was delivered at moderate-vigorous intensity and supervised by an exercise specialist. For schizophrenia-spectrum disorders, evidence indicates that aerobic PA can reduce psychiatric symptoms, improves cognition and various subdomains, cardiorespiratory fitness, whilst evidence for the impact on anthropometric measures was inconsistent. There was a paucity of studies investigating PA in bipolar disorder, precluding any definitive recommendations. No cost effectiveness analyses in any SMI condition were identified. We make multiple recommendations to fill existing research gaps and increase the use of PA in routine clinical care aimed at improving psychiatric and medical outcomes.
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