| 1. |
|
|
| 2. |
- Le Clerc, S., et al.
(författare)
-
HLA-DRB1 and HLA-DQB1 genetic diversity modulates response to lithium in bipolar affective disorders
- 2021
-
Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 11:1
-
Tidskriftsartikel (refereegranskat)abstract
- Bipolar affective disorder (BD) is a severe psychiatric illness, for which lithium (Li) is the gold standard for acute and maintenance therapies. The therapeutic response to Li in BD is heterogeneous and reliable biomarkers allowing patients stratification are still needed. A GWAS performed by the International Consortium on Lithium Genetics (ConLiGen) has recently identified genetic markers associated with treatment responses to Li in the human leukocyte antigens (HLA) region. To better understand the molecular mechanisms underlying this association, we have genetically imputed the classical alleles of the HLA region in the European patients of the ConLiGen cohort. We found our best signal for amino-acid variants belonging to the HLA-DRB1*11:01 classical allele, associated with a better response to Li (p < 1 x 10(-3); FDR < 0.09 in the recessive model). Alanine or Leucine at position 74 of the HLA-DRB1 heavy chain was associated with a good response while Arginine or Glutamic acid with a poor response. As these variants have been implicated in common inflammatory/autoimmune processes, our findings strongly suggest that HLA-mediated low inflammatory background may contribute to the efficient response to Li in BD patients, while an inflammatory status overriding Li anti-inflammatory properties would favor a weak response.
|
|
| 3. |
- Reinbold, C. S., et al.
(författare)
-
Analysis of the Influence of microRNAs in Lithium Response in Bipolar Disorder
- 2018
-
Ingår i: Frontiers in Psychiatry. - : Frontiers Media SA. - 1664-0640. ; 9
-
Tidskriftsartikel (refereegranskat)abstract
- Bipolar disorder (BD) is a common, highly heritable neuropsychiatric disease characterized by recurrent episodes of mania and depression. Lithium is the best-established long-term treatment for BD, even though individual response is highly variable Evidence suggests that some of this variability has a genetic basis. This is supported by the largest genome-wide association study (GWAS) of lithium response to date conducted by the International Consortium on Lithium Genetics (ConLiGen) Recently, we performed the first genome-wide analysis of the involvement of miRNAs in BD and identified nine BD associated miRNAs However, it is unknown whether these miRNAs are also associated with lithium response in BD. In the present study, we therefore tested whether common variants at these nine candidate miRNAs contribute to the variance in lithium response in BD. Furthermore, we systematically analyzed whether any other miRNA in the genome is implicated in the response to lithium. For this purpose, we performed gene-based tests for all known miRNA coding genes in the ConLiGen GWAS dataset (n = 2,563 patients) using a set-based testing approach adapted from the versatile gene based test for GWAS (VEGAS2). In the candidate approach, miR-499a showed a nominally significant association with lithium response, providing some evidence for involvement in both development and treatment of BD. In the genome-wide miRNA analysis, 71 miRNAs showed nominally significant associations with the dichotomous phenotype and 106 with the continuous trait for treatment response. A total of 15 miRNAs revealed nominal significance in both phenotypes with miR-633 showing the strongest association with the continuous trait (p = 9.80E-04) and miR-607 with the dichotomous phenotype (p = 5.79E-04). No association between miRNAs and treatment response to lithium in BD in either of the tested conditions withstood multiple testing correction. Given the limited power of our study, the investigation of miRNAs in larger GWAS samples of BD and lithium response is warranted.
|
|
| 4. |
- Schubert, K. O., et al.
(författare)
-
Combining schizophrenia and depression polygenic risk scores improves the genetic prediction of lithium response in bipolar disorder patients
- 2021
-
Ingår i: Translational Psychiatry. - : Springer Science and Business Media LLC. - 2158-3188. ; 11:1
-
Tidskriftsartikel (refereegranskat)abstract
- Lithium is the gold standard therapy for Bipolar Disorder (BD) but its effectiveness differs widely between individuals. The molecular mechanisms underlying treatment response heterogeneity are not well understood, and personalized treatment in BD remains elusive. Genetic analyses of the lithium treatment response phenotype may generate novel molecular insights into lithium's therapeutic mechanisms and lead to testable hypotheses to improve BD management and outcomes. We used fixed effect meta-analysis techniques to develop meta-analytic polygenic risk scores (MET-PRS) from combinations of highly correlated psychiatric traits, namely schizophrenia (SCZ), major depression (MD) and bipolar disorder (BD). We compared the effects of cross-disorder MET-PRS and single genetic trait PRS on lithium response. For the PRS analyses, we included clinical data on lithium treatment response and genetic information for n = 2283 BD cases from the International Consortium on Lithium Genetics (ConLi(+)Gen; ). Higher SCZ and MD PRSs were associated with poorer lithium treatment response whereas BD-PRS had no association with treatment outcome. The combined MET2-PRS comprising of SCZ and MD variants (MET2-PRS) and a model using SCZ and MD-PRS sequentially improved response prediction, compared to single-disorder PRS or to a combined score using all three traits (MET3-PRS). Patients in the highest decile for MET2-PRS loading had 2.5 times higher odds of being classified as poor responders than patients with the lowest decile MET2-PRS scores. An exploratory functional pathway analysis of top MET2-PRS variants was conducted. Findings may inform the development of future testing strategies for personalized lithium prescribing in BD.
|
|
| 5. |
- Amare, A. T., et al.
(författare)
-
Association of polygenic score for major depression with response to lithium in patients with bipolar disorder
- 2021
-
Ingår i: Molecular Psychiatry. - : Springer Science and Business Media LLC. - 1359-4184 .- 1476-5578. ; 26, s. 2457-2470
-
Tidskriftsartikel (refereegranskat)abstract
- Lithium is a first-line medication for bipolar disorder (BD), but only one in three patients respond optimally to the drug. Since evidence shows a strong clinical and genetic overlap between depression and bipolar disorder, we investigated whether a polygenic susceptibility to major depression is associated with response to lithium treatment in patients with BD. Weighted polygenic scores (PGSs) were computed for major depression (MD) at different GWAS p value thresholds using genetic data obtained from 2586 bipolar patients who received lithium treatment and took part in the Consortium on Lithium Genetics (ConLi(+)Gen) study. Summary statistics from genome-wide association studies in MD (135,458 cases and 344,901 controls) from the Psychiatric Genomics Consortium (PGC) were used for PGS weighting. Response to lithium treatment was defined by continuous scores and categorical outcome (responders versus non-responders) using measurements on the Alda scale. Associations between PGSs of MD and lithium treatment response were assessed using a linear and binary logistic regression modeling for the continuous and categorical outcomes, respectively. The analysis was performed for the entire cohort, and for European and Asian sub-samples. The PGSs for MD were significantly associated with lithium treatment response in multi-ethnic, European or Asian populations, at various p value thresholds. Bipolar patients with a low polygenic load for MD were more likely to respond well to lithium, compared to those patients with high polygenic load [lowest vs highest PGS quartiles, multi-ethnic sample: OR = 1.54 (95% CI: 1.18-2.01) and European sample: OR = 1.75 (95% CI: 1.30-2.36)]. While our analysis in the Asian sample found equivalent effect size in the same direction: OR = 1.71 (95% CI: 0.61-4.90), this was not statistically significant. Using PGS decile comparison, we found a similar trend of association between a high genetic loading for MD and lower response to lithium. Our findings underscore the genetic contribution to lithium response in BD and support the emerging concept of a lithium-responsive biotype in BD.
|
|
| 6. |
- Cearns, M., et al.
(författare)
-
Using polygenic scores and clinical data for bipolar disorder patient stratification and lithium response prediction: machine learning approach
- 2022
-
Ingår i: British Journal of Psychiatry. - : Royal College of Psychiatrists. - 0007-1250 .- 1472-1465. ; 220:4, s. 219-228
-
Tidskriftsartikel (refereegranskat)abstract
- Background Response to lithium in patients with bipolar disorder is associated with clinical and transdiagnostic genetic factors. The predictive combination of these variables might help clinicians better predict which patients will respond to lithium treatment. Aims To use a combination of transdiagnostic genetic and clinical factors to predict lithium response in patients with bipolar disorder. Method This study utilised genetic and clinical data (n = 1034) collected as part of the International Consortium on Lithium Genetics (ConLi(+)Gen) project. Polygenic risk scores (PRS) were computed for schizophrenia and major depressive disorder, and then combined with clinical variables using a cross-validated machine-learning regression approach. Unimodal, multimodal and genetically stratified models were trained and validated using ridge, elastic net and random forest regression on 692 patients with bipolar disorder from ten study sites using leave-site-out cross-validation. All models were then tested on an independent test set of 342 patients. The best performing models were then tested in a classification framework. Results The best performing linear model explained 5.1% (P = 0.0001) of variance in lithium response and was composed of clinical variables, PRS variables and interaction terms between them. The best performing non-linear model used only clinical variables and explained 8.1% (P = 0.0001) of variance in lithium response. A priori genomic stratification improved non-linear model performance to 13.7% (P = 0.0001) and improved the binary classification of lithium response. This model stratified patients based on their meta-polygenic loadings for major depressive disorder and schizophrenia and was then trained using clinical data. Conclusions Using PRS to first stratify patients genetically and then train machine-learning models with clinical predictors led to large improvements in lithium response prediction. When used with other PRS and biological markers in the future this approach may help inform which patients are most likely to respond to lithium treatment.
|
|
| 7. |
- Jonsson, Lina, 1982, et al.
(författare)
-
Characterisation of age and polarity at onset in bipolar disorder
- 2021
-
Ingår i: British Journal of Psychiatry. - : Royal College of Psychiatrists. - 0007-1250 .- 1472-1465. ; 219:6, s. 659-669
-
Tidskriftsartikel (refereegranskat)abstract
- Background Studying phenotypic and genetic characteristics of age at onset (AAO) and polarity at onset (PAO) in bipolar disorder can provide new insights into disease pathology and facilitate the development of screening tools. Aims To examine the genetic architecture of AAO and PAO and their association with bipolar disorder disease characteristics. Method Genome-wide association studies (GWASs) and polygenic score (PGS) analyses of AAO (n = 12 977) and PAO (n = 6773) were conducted in patients with bipolar disorder from 34 cohorts and a replication sample (n = 2237). The association of onset with disease characteristics was investigated in two of these cohorts. Results Earlier AAO was associated with a higher probability of psychotic symptoms, suicidality, lower educational attainment, not living together and fewer episodes. Depressive onset correlated with suicidality and manic onset correlated with delusions and manic episodes. Systematic differences in AAO between cohorts and continents of origin were observed. This was also reflected in single-nucleotide variant-based heritability estimates, with higher heritabilities for stricter onset definitions. Increased PGS for autism spectrum disorder (beta = -0.34 years, s.e. = 0.08), major depression (beta = -0.34 years, s.e. = 0.08), schizophrenia (beta = -0.39 years, s.e. = 0.08), and educational attainment (beta = -0.31 years, s.e. = 0.08) were associated with an earlier AAO. The AAO GWAS identified one significant locus, but this finding did not replicate. Neither GWAS nor PGS analyses yielded significant associations with PAO. Conclusions AAO and PAO are associated with indicators of bipolar disorder severity. Individuals with an earlier onset show an increased polygenic liability for a broad spectrum of psychiatric traits. Systematic differences in AAO across cohorts, continents and phenotype definitions introduce significant heterogeneity, affecting analyses.
|
|
| 8. |
- Wasserman, D, et al.
(författare)
-
Compulsory admissions of patients with mental disorders: State of the art on ethical and legislative aspects in 40 European countries
- 2020
-
Ingår i: European psychiatry : the journal of the Association of European Psychiatrists. - : Royal College of Psychiatrists. - 1778-3585. ; 63:1, s. e82-
-
Tidskriftsartikel (refereegranskat)abstract
- Background.Compulsory admission procedures of patients with mental disorders vary between countries in Europe. The Ethics Committee of the European Psychiatric Association (EPA) launched a survey on involuntary admission procedures of patients with mental disorders in 40 countries to gather information from all National Psychiatric Associations that are members of the EPA to develop recommendations for improving involuntary admission processes and promote voluntary care.Methods.The survey focused on legislation of involuntary admissions and key actors involved in the admission procedure as well as most common reasons for involuntary admissions.Results.We analyzed the survey categorical data in themes, which highlight that both medical and legal actors are involved in involuntary admission procedures.Conclusions.We conclude that legal reasons for compulsory admission should be reworded in order to remove stigmatization of the patient, that raising awareness about involuntary admission procedures and patient rights with both patients and family advocacy groups is paramount, that communication about procedures should be widely available in lay-language for the general population, and that training sessions and guidance should be available for legal and medical practitioners. Finally, people working in the field need to be constantly aware about the ethical challenges surrounding compulsory admissions.
|
|
| 9. |
|
|
| 10. |
|
|
| 11. |
|
|
| 12. |
|
|
| 13. |
|
|
| 14. |
- Kalman, JL, et al.
(författare)
-
Investigating the phenotypic and genetic associations between personality traits and suicidal behavior across major mental health diagnoses
- 2022
-
Ingår i: European archives of psychiatry and clinical neuroscience. - : Springer Science and Business Media LLC. - 1433-8491 .- 0940-1334. ; 272:8, s. 1611-1620
-
Tidskriftsartikel (refereegranskat)abstract
- Personality traits influence risk for suicidal behavior. We examined phenotype- and genotype-level associations between the Big Five personality traits and suicidal ideation and attempt in major depressive, bipolar and schizoaffective disorder, and schizophrenia patients (N = 3012) using fixed- and random-effects inverse variance-weighted meta-analyses. Suicidal ideations were more likely to be reported by patients with higher neuroticism and lower extraversion phenotypic scores, but showed no significant association with polygenic load for these personality traits. Our findings provide new insights into the association between personality and suicidal behavior across mental illnesses and suggest that the genetic component of personality traits is unlikely to have strong causal effects on suicidal behavior.
|
|
| 15. |
|
|
| 16. |
|
|
| 17. |
- Hasan, A, et al.
(författare)
-
World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for Biological Treatment of Schizophrenia : Part 1: Update 2012 on the acute treatment of schizophrenia and the management of treatment resistance.
- 2012
-
Ingår i: The World Journal of Biological Psychiatry. - : Informa UK Limited. - 1562-2975 .- 1814-1412. ; 13:5, s. 318-378
-
Tidskriftsartikel (refereegranskat)abstract
- These updated guidelines are based on a first edition of the World Federation of Societies of Biological Psychiatry Guidelines for Biological Treatment of Schizophrenia published in 2005. For this 2012 revision, all available publications pertaining to the biological treatment of schizophrenia were reviewed systematically to allow for an evidence-based update. These guidelines provide evidence-based practice recommendations that are clinically and scientifically meaningful and these guidelines are intended to be used by all physicians diagnosing and treating people suffering from schizophrenia. Based on the first version of these guidelines, a systematic review of the MEDLINE/PUBMED database and the Cochrane Library, in addition to data extraction from national treatment guidelines, has been performed for this update. The identified literature was evaluated with respect to the strength of evidence for its efficacy and then categorised into six levels of evidence (A–F; Bandelow et al. 2008b, World J Biol Psychiatry 9:242). This first part of the updated guidelines covers the general descriptions of antipsychotics and their side effects, the biological treatment of acute schizophrenia and the management of treatment-resistant schizophrenia.
|
|
| 18. |
- Schmitt, A, et al.
(författare)
-
How a neuropsychiatric brain bank should be run : a consensus paper of Brainnet Europe II.
- 2007
-
Ingår i: Journal of neural transmission. - : Springer Science and Business Media LLC. - 0300-9564 .- 1435-1463. ; 114:5, s. 527-37
-
Tidskriftsartikel (refereegranskat)abstract
- The development of new molecular and neurobiological methods, computer-assisted quantification techniques and neurobiological investigation methods which can be applied to the human brain, all have evoked an increased demand for post-mortem tissue in research. Psychiatric disorders are considered to be of neurobiological origin. Thus far, however, the etiology and pathophysiology of schizophrenia, depression and dementias are not well understood at the cellular and molecular level. The following will outline the consensus of the working group for neuropsychiatric brain banking organized in the Brainnet Europe II, on ethical guidelines for brain banking, clinical diagnostic criteria, the minimal clinical data set of retrospectively analyzed cases as well as neuropathological standard investigations to perform stageing for neurodegenerative disorders in brain tissue. We will list regions of interest for assessments in psychiatric disorder, propose a dissection scheme and describe preservation and storage conditions of tissue. These guidelines may be of value for future implementations of additional neuropsychiatric brain banks world-wide.
|
|
| 19. |
|
|
| 20. |
|
|
| 21. |
|
|
| 22. |
- Jobst, A, et al.
(författare)
-
European Psychiatric Association Guidance on psychotherapy in chronic depression across Europe
- 2016
-
Ingår i: European psychiatry : the journal of the Association of European Psychiatrists. - : Cambridge University Press (CUP). - 1778-3585. ; 33, s. 18-36
-
Tidskriftsartikel (refereegranskat)abstract
- PurposePatients with chronic depression (CD) by definition respond less well to standard forms of psychotherapy and are more likely to be high utilizers of psychiatric resources. Therefore, the aim of this guidance paper is to provide a comprehensive overview of current psychotherapy for CD. The evidence of efficacy is critically reviewed and recommendations for clinical applications and research are given.MethodsWe performed a systematic literature search to identify studies on psychotherapy in CD, evaluated the retrieved documents and developed evidence tables and recommendations through a consensus process among experts and stakeholders.ResultsWe developed 5 recommendations which may help providers to select psychotherapeutic treatment options for this patient group. The EPA considers both psychotherapy and pharmacotherapy to be effective in CD and recommends both approaches. The best effect is achieved by combined treatment with psychotherapy and pharmacotherapy, which should therefore be the treatment of choice. The EPA recommends psychotherapy with an interpersonal focus (e.g. the Cognitive Behavioural Analysis System of Psychotherapy [CBASP]) for the treatment of CD and a personalized approach based on the patient's preferences.DiscussionThe DSM-5 nomenclature of persistent depressive disorder (PDD), which includes CD subtypes, has been an important step towards a more differentiated treatment and understanding of these complex affective disorders. Apart from dysthymia, ICD-10 still does not provide a separate entity for a chronic course of depression. The differences between patients with acute episodic depression and those with CD need to be considered in the planning of treatment. Specific psychotherapeutic treatment options are recommended for patients with CD.ConclusionPatients with chronic forms of depression should be offered tailored psychotherapeutic treatments that address their specific needs and deficits. Combination treatment with psychotherapy and pharmacotherapy is the first-line treatment recommended for CD. More research is needed to develop more effective treatments for CD, especially in the longer term, and to identify which patients benefit from which treatment algorithm.
|
|
| 23. |
|
|
| 24. |
- Monoranu, Camelia Maria, et al.
(författare)
-
pH measurement as quality control on human post mortem brain tissue : a study of the BrainNet Europe consortium
- 2009
-
Ingår i: Neuropathology and Applied Neurobiology. - : Wiley. - 0305-1846 .- 1365-2990. ; 35:3, s. 329-337
-
Tidskriftsartikel (refereegranskat)abstract
- AIMS: Most brain diseases are complex entities. Although animal models or cell culture experiments mimic some disease aspects, human post mortem brain tissue remains essential to advance our understanding of brain diseases using biochemical and molecular techniques. Post mortem artefacts must be properly understood, standardized, and either eliminated or factored into such experiments. Here we examine the influence of several premortem and post mortem factors on pH, and discuss the role of pH as a biochemical marker for brain tissue quality. METHODS: We assessed brain tissue pH in 339 samples from 116 brains provided by 8 different European and 2 Australian brain bank centres. We correlated brain pH with tissue source, post mortem delay, age, gender, freezing method, storage duration, agonal state and brain ischaemia. RESULTS: Our results revealed that only prolonged agonal state and ischaemic brain damage influenced brain tissue pH next to repeated freeze/thaw cycles. CONCLUSIONS: pH measurement in brain tissue is a good indicator of premortem events in brain tissue and it signals limitations for post mortem investigations.
|
|
| 25. |
|
|
| 26. |
- Amare, Azmeraw T, et al.
(författare)
-
Association of polygenic score and the involvement of cholinergic and glutamatergic pathways with lithium treatment response in patients with bipolar disorder.
- 2023
-
Ingår i: Molecular psychiatry. - 1476-5578. ; 28, s. 5251-5261
-
Tidskriftsartikel (refereegranskat)abstract
- Lithium is regarded as the first-line treatment for bipolar disorder (BD), a severe and disabling mental healthdisorder that affects about 1% of the population worldwide. Nevertheless, lithium is not consistently effective, with only 30% of patients showing a favorable response to treatment. To provide personalized treatment options for bipolar patients, it is essential to identify prediction biomarkers such as polygenic scores. In this study, we developed a polygenic score for lithium treatment response (Li+PGS) in patients with BD. To gain further insights into lithium's possible molecular mechanism of action, we performed a genome-wide gene-based analysis. Using polygenic score modeling, via methods incorporating Bayesian regression and continuous shrinkage priors, Li+PGS was developed in the International Consortium of Lithium Genetics cohort (ConLi+Gen: N=2367) and replicated in the combined PsyCourse (N=89) and BipoLife (N=102) studies. The associations of Li+PGS and lithium treatment response - defined in a continuous ALDA scale and a categorical outcome (good response vs. poor response) were tested using regression models, each adjusted for the covariates: age, sex, and the first four genetic principal components. Statistical significance was determined at P<0.05. Li+PGS was positively associated with lithium treatment response in the ConLi+Gen cohort, in both the categorical (P=9.8×10-12, R2=1.9%) and continuous (P=6.4×10-9, R2=2.6%) outcomes. Compared to bipolar patients in the 1st decile of the risk distribution, individuals in the 10th decile had 3.47-fold (95%CI: 2.22-5.47) higher odds of responding favorably to lithium. The results were replicated in the independent cohorts for the categorical treatment outcome (P=3.9×10-4, R2=0.9%), but not for the continuous outcome (P=0.13). Gene-based analyses revealed 36 candidate genes that are enriched in biological pathways controlled by glutamate and acetylcholine. Li+PGS may be useful in the development of pharmacogenomic testing strategies by enabling a classification of bipolar patients according to their response to treatment.
|
|
| 27. |
- Amare, Azmeraw T, et al.
(författare)
-
Association of Polygenic Score for Schizophrenia and HLA Antigen and Inflammation Genes With Response to Lithium in Bipolar Affective Disorder: A Genome-Wide Association Study.
- 2018
-
Ingår i: JAMA psychiatry. - : American Medical Association (AMA). - 2168-6238 .- 2168-622X. ; 75:1, s. 65-74
-
Tidskriftsartikel (refereegranskat)abstract
- Lithium is a first-line mood stabilizer for the treatment of bipolar affective disorder (BPAD). However, the efficacy of lithium varies widely, with a nonresponse rate of up to 30%. Biological response markers are lacking. Genetic factors are thought to mediate treatment response to lithium, and there is a previously reported genetic overlap between BPAD and schizophrenia (SCZ).To test whether a polygenic score for SCZ is associated with treatment response to lithium in BPAD and to explore the potential molecular underpinnings of this association.A total of 2586 patients with BPAD who had undergone lithium treatment were genotyped and assessed for long-term response to treatment between 2008 and 2013. Weighted SCZ polygenic scores were computed at different P value thresholds using summary statistics from an international multicenter genome-wide association study (GWAS) of 36989 individuals with SCZ and genotype data from patients with BPAD from the Consortium on Lithium Genetics. For functional exploration, a cross-trait meta-GWAS and pathway analysis was performed, combining GWAS summary statistics on SCZ and response to treatment with lithium. Data analysis was performed from September 2016 to February 2017.Treatment response to lithium was defined on both the categorical and continuous scales using the Retrospective Criteria of Long-Term Treatment Response in Research Subjects with Bipolar Disorder score. The effect measures include odds ratios and the proportion of variance explained.Of the 2586 patients in the study (mean [SD] age, 47.2 [13.9] years), 1478 were women and 1108 were men. The polygenic score for SCZ was inversely associated with lithium treatment response in the categorical outcome, at a threshold P<5×10-2. Patients with BPAD who had a low polygenic load for SCZ responded better to lithium, with odds ratios for lithium response ranging from 3.46 (95% CI, 1.42-8.41) at the first decile to 2.03 (95% CI, 0.86-4.81) at the ninth decile, compared with the patients in the 10th decile of SCZ risk. In the cross-trait meta-GWAS, 15 genetic loci that may have overlapping effects on lithium treatment response and susceptibility to SCZ were identified. Functional pathway and network analysis of these loci point to the HLA antigen complex and inflammatory cytokines.This study provides evidence for a negative association between high genetic loading for SCZ and poor response to lithium in patients with BPAD. These results suggest the potential for translational research aimed at personalized prescribing of lithium.
|
|
| 28. |
|
|
| 29. |
- Coombes, Brandon J, et al.
(författare)
-
Association of Attention-Deficit/Hyperactivity Disorder and Depression Polygenic Scores with Lithium Response: A Consortium for Lithium Genetics Study.
- 2021
-
Ingår i: Complex psychiatry. - : S. Karger AG. - 2673-3005 .- 2673-298X. ; 7:3-4, s. 80-89
-
Tidskriftsartikel (refereegranskat)abstract
- Response to lithium varies widely between individuals with bipolar disorder (BD). Polygenic risk scores (PRSs) can uncover pharmacogenomics effects and may help predict drug response. Patients (N = 2,510) with BD were assessed for long-term lithium response in the Consortium on Lithium Genetics using the Retrospective Criteria of Long-Term Treatment Response in Research Subjects with Bipolar Disorder score. PRSs for attention-deficit/hyperactivity disorder (ADHD), major depressive disorder (MDD), and schizophrenia (SCZ) were computed using lassosum and in a model including all three PRSs and other covariates, and the PRS of ADHD (β = -0.14; 95% confidence interval [CI]: -0.24 to -0.03; p value = 0.010) and MDD (β = -0.16; 95% CI: -0.27 to -0.04; p value = 0.005) predicted worse quantitative lithium response. A higher SCZ PRS was associated with higher rates of medication nonadherence (OR = 1.61; 95% CI: 1.34-1.93; p value = 2e-7). This study indicates that genetic risk for ADHD and depression may influence lithium treatment response. Interestingly, a higher SCZ PRS was associated with poor adherence, which can negatively impact treatment response. Incorporating genetic risk of ADHD, depression, and SCZ in combination with clinical risk may lead to better clinical care for patients with BD.
|
|
| 30. |
|
|
| 31. |
- Herrera-Rivero, Marisol, et al.
(författare)
-
Exploring the genetics of lithium response in bipolar disorders.
- 2023
-
Ingår i: Research square.
-
Annan publikation (övrigt vetenskapligt/konstnärligt)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.
|
|
| 32. |
|
|
| 33. |
- Hou, Liping, et al.
(författare)
-
Genome-wide association study of 40,000 individuals identifies two novel loci associated with bipolar disorder.
- 2016
-
Ingår i: Human molecular genetics. - : Oxford University Press (OUP). - 1460-2083 .- 0964-6906. ; 25:15, s. 3383-94
-
Tidskriftsartikel (refereegranskat)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.
|
|
| 34. |
- Kalman, Janos L, et al.
(författare)
-
Investigating polygenic burden in age at disease onset in bipolar disorder: Findings from an international multicentric study.
- 2019
-
Ingår i: Bipolar disorders. - : Wiley. - 1399-5618 .- 1398-5647. ; 21:1, s. 68-75
-
Tidskriftsartikel (refereegranskat)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.
|
|
| 35. |
|
|
| 36. |
- Matosin, N, et al.
(författare)
-
Associations of psychiatric disease and ageing with FKBP5 expression converge on superficial layer neurons of the neocortex
- 2023
-
Ingår i: Acta neuropathologica. - : Springer Science and Business Media LLC. - 1432-0533 .- 0001-6322. ; 145:4, s. 439-459
-
Tidskriftsartikel (refereegranskat)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.
|
|
| 37. |
|
|
| 38. |
- Mayer, S, et al.
(författare)
-
European Psychiatric Association (EPA) guidance on post-graduate psychiatric training in Europe
- 2014
-
Ingår i: European psychiatry : the journal of the Association of European Psychiatrists. - : Cambridge University Press (CUP). - 1778-3585. ; 29:2, s. 101-106
-
Tidskriftsartikel (refereegranskat)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.
|
|
| 39. |
- Ou, Anna H., et al.
(författare)
-
Lithium response in bipolar disorder is associated with focal adhesion and PI3K-Akt networks: a multi-omics replication study
- 2024
-
Ingår i: TRANSLATIONAL PSYCHIATRY. - 2158-3188. ; 14:1
-
Tidskriftsartikel (refereegranskat)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.
|
|
| 40. |
- Stubbs, B, et al.
(författare)
-
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
-
Ingår i: European psychiatry : the journal of the Association of European Psychiatrists. - : Cambridge University Press (CUP). - 1778-3585. ; 54, s. 124-144
-
Tidskriftsartikel (refereegranskat)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.
|
|
| 41. |
- Wagner, E, et al.
(författare)
-
Clozapine Optimization: A Delphi Consensus Guideline From the Treatment Response and Resistance in Psychosis Working Group
- 2023
-
Ingår i: Schizophrenia bulletin. - : Oxford University Press (OUP). - 1745-1701 .- 0586-7614. ; 49:4, s. 962-972
-
Tidskriftsartikel (refereegranskat)abstract
- Background and HypothesisThere is limited evidence to guide the approaches to clozapine treatment. Accordingly, an international initiative was undertaken with the aim of developing consensus recommendations for the optimization of clozapine monotherapy.Study DesignWe conducted an online Delphi survey among members of the Treatment Response and Resistance in Psychosis (TRRIP) working group comprising experts from twenty-nine countries. The threshold criterion for a consensus recommendation was ≥ 75% agreement (“agree” and “strongly agree” responses) on a question. Agreement of ≥ 50% but < 75% in a second or third Delphi round was deemed to provide guidance.Study ResultsForty-nine (first round), 32 (second round), and 48 (third round) of the 91 current TRRIP members participated. Expert recommendations at ≥ 75% comprised second-line treatment with clozapine in cases of persistent positive symptoms with co-occurring extrapyramidal symptoms, tardive dyskinesia, or suicidality/aggression. There was considerable disagreement on myocarditis screening parameters. The management of somatic and neuropsychiatric adverse drug reactions warrants further research for more evidence-based recommendations. Rechallenge with clozapine was recommended for eosinophilia, sinus tachycardia and fever and guidance (agreement ≥ 50%) was reached for pneumonia and thrombocytopenia.ConclusionsGiven the limited evidence available, this consensus-based series of recommendations and guidance statements supports clinical decision-making to optimize clozapine monotherapy and provides guidance for future research in treatment-resistant schizophrenia.
|
|
