| 1. |
- Amare, Azmeraw, et al.
(author)
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Association of Polygenic Score and the involvement of Cholinergic and Glutamatergic Pathways with Lithium Treatment Response in Patients with Bipolar Disorder.
- 2023
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In: Research square. - : Research Square Platform LLC.
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Journal article (peer-reviewed)abstract
- Lithium is regarded as the first-line treatment for bipolar disorder (BD), a severe and disabling mental disorder 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=2,367) 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<����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������.
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| 2. |
- Amare, Azmeraw T, et al.
(author)
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Association of polygenic score and the involvement of cholinergic and glutamatergic pathways with lithium treatment response in patients with bipolar disorder.
- 2023
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In: Molecular psychiatry. - 1476-5578. ; 28, s. 5251-5261
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Journal article (peer-reviewed)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.
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| 3. |
- Amare, A. T., et al.
(author)
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Association of polygenic score for major depression with response to lithium in patients with bipolar disorder
- 2021
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In: Molecular Psychiatry. - : Springer Science and Business Media LLC. - 1359-4184 .- 1476-5578. ; 26, s. 2457-2470
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Journal article (peer-reviewed)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.
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| 4. |
- Amare, Azmeraw T, et al.
(author)
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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
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In: JAMA psychiatry. - : American Medical Association (AMA). - 2168-6238 .- 2168-622X. ; 75:1, s. 65-74
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Journal article (peer-reviewed)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.
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| 5. |
- Andersson, Ulrika, et al.
(author)
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PERson-centredness in Hypertension management using Information Technology: a randomized controlled trial in primary care
- 2023
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In: Journal of hypertension. - : LIPPINCOTT WILLIAMS & WILKINS. - 1473-5598 .- 0263-6352. ; 41:2, s. 246-253
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Journal article (peer-reviewed)abstract
- OBJECTIVES: To increase the proportion of individuals with hypertension obtaining a blood pressure (BP) of less than 140/90mmHg by improving the management of hypertension in daily life from a person-centred perspective. METHODS: In this unblinded randomized controlled trial, we tested an interactive web-based self-management system for hypertension. A total of 949 patients with hypertension from 31 primary healthcare centres (PHCCs) in Sweden were randomized 1:1 to either the intervention or usual care group. The intervention included daily measurement - via the participant's mobile phone - of BP and pulse and reports of well being, symptoms, lifestyle, medication intake and side effects for eight consecutive weeks. It also included reminders and optional motivational messages. The primary outcome was the proportion of participants obtaining BP of less than 140/90mmHg at 8 weeks and 12months. Significance was tested by Pearson's chi 2 -test. RESULTS: A total of 862 patients completed the trial, 442 in the intervention group and 420 in the control group. The primary outcome (BP <140/90mmHg) at 8 weeks was achieved by 48.8% in the intervention group and 39.9% in the control group ( P =0.006). At 12months, 47.1% (intervention) and 41.0% (control group) had a BP less than 140/90mmHg ( P =0.071). CONCLUSION: The proportion of participants with a controlled BP of less than 140/90mmHg increased after using the interactive system for self-management of hypertension for 8 weeks compared with usual care. Although the trend continued, there was no significant difference after 12months. The results indicate that the effect of the intervention is significant, but the long-term effect is uncertain. TRIAL REGISTRATION: The study was registered with ClinicalTrials.gov (NCT03554382).
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| 6. |
- Andersson, Ulrika, et al.
(author)
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PERSON-CENTREDNESS IN HYPERTENSION MANAGEMENT USING INFORMATION TECHNOLOGY (PERHIT) : A RANDOMISED CONTROLLED TRIAL IN PRIMARY HEALTH CARE
- 2022
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In: Journal of Hypertension. - : Ovid Technologies (Wolters Kluwer Health). - 1473-5598 .- 0263-6352. ; 40, s. 197-197
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Conference paper (other academic/artistic)abstract
- OBJECTIVE: Few studies address results from use of new technology and patient participation in hypertension management. The PERHIT Study is a multicentre randomised controlled trial with the aim to evaluate the effects of a person-centred approach using a web-based, interactive self-management system through the patient´s own mobile phone on blood-pressure and well-being. Primary aim is the degree of achieved blood pressure (BP) control after eight weeks and one year. In addition, person-centeredness, usefulness, daily life activities in relation to BP values, awareness of risk and health care costs are studied. DESIGN AND METHOD: The PERHIT study was performed in four regions in southern Sweden. Following inclusion, more than 900 patients from 31 primary health care centres were randomised to two groups. In the intervention group (INT), patients were provided with a web-based self-management support system including a home-BP monitor. For eight consecutive weeks, they measured BP and performed self-reports regarding well-being, symptoms, lifestyle, medication intake and side effects every evening via their mobile phone. They could also receive motivational messages and reminders throughout the intervention period. Both patients and professionals had access to graphic feedback of reported values through a secure web portal. Patients in the control (CON) group received standard treatment as usual. RESULTS: The primary outcome (BP < 140/90 mmHg) was achieved by 48.5% and 47.1% in the INT, and by 40.4% and 40.9% in the CON group after 8 weeks (p = 0.016) and 12 months (p = 0.067), respectively. Both patients and professionals experienced the system as a useful resource for communication regarding BP and lifestyle. They described that it could be used to support a constructive and person-centred partnership between patients and professionals. CONCLUSIONS: Blood pressure control was significantly better after eight weeks, but not after one year, following an intervention based on use of mobile phones, feedback and interaction between patients and primary care professionals compared to standard care. The system can be a tool toward a new way of working and help patients reach a controlled BP and play a role in a more person-centred and individually adapted hypertension management.
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| 7. |
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| 8. |
- Björkman Lundberg, Kerstin, et al.
(author)
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Compliance to National Guidelines for Pharmaceutical Treatment of Sleeping Disorders among Elderly Incident Patients in Sweden in PHARMACOEPIDEMIOLOGY AND DRUG SAFETY, vol 20, issue , pp S203-S203
- 2011
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In: PHARMACOEPIDEMIOLOGY AND DRUG SAFETY. - : John Wiley and Sons. ; , s. S203-S203
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Conference paper (peer-reviewed)abstract
- Background:National guidelines for pharmaceutical treatmentof sleeping disorders among elderly state that zopicloneshould be the first choice and that other hypnotics,such as long acting benzodiazepines and propiomazine,should be avoided. According to aggregated data describingprevalent users compliance to guidelines is fairly high. Objectives:The objective of this study was to investigatechoice and volume (DDD) of substance among incidentusers 75 years and older (75+) of hypnotics (N05C) in Swedenand compare between different county councils andwith incident users below 75 years of age. Methods:Data from the Swedish Prescribed Drug registercovering all dispensed prescriptions in Sweden was analyzedfor incident users of hypnotics (15–44, 45–64, 65–74 and 75+ years of age). Incident users were defined aspeople who filled a prescription (index date) of a hypnotic(N05C) during the period December 2009 - November2010 and had not filled any prescription for a hypnotic duringa wash-out period of 24 months before the index date. Results:Among incident patients 75+ (n= 38,620) zopiclone(52.9%), zolpidem (25.4%), and propiomazine(10.4%) were the most frequently used hypnotics. Therewere however differences between different county councilsin Sweden, with zopiclone ranging from 30 % to 68 %. Theincidence for recommended and appropriate hypnoticsincreased with increasing age, whereas the incidence ofinappropriate hypnotics did not. The prescribed volume ofinappropriate hypnotics was generally larger than the prescribedvolume of recommended hypnotics. Conclusions:The compliance to current guidelines onchoice of hypnotics for the elderly is fairly good, althoughthere is considerable variation between county councils.There are tendencies towards larger mean volumes of inappropriatehypnotics, although further studies are needed toconfirm these findings. Another aspect of quality in treatmentwith sleeping agents is to which extent incident userscontinue their treatment and for how long. This is an issuefor further research.
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| 9. |
- Blokland, G. A. M., et al.
(author)
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Sex-Dependent Shared and Nonshared Genetic Architecture Across Mood and Psychotic Disorders
- 2022
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In: Biological Psychiatry. - : Elsevier BV. - 0006-3223 .- 1873-2402. ; 91:1, s. 102-117
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Journal article (peer-reviewed)abstract
- Background: Sex differences in incidence and/or presentation of schizophrenia (SCZ), major depressive disorder (MDD), and bipolar disorder (BIP) are pervasive. Previous evidence for shared genetic risk and sex differences in brain abnormalities across disorders suggest possible shared sex-dependent genetic risk. Methods: We conducted the largest to date genome-wide genotype-by-sex (G×S) interaction of risk for these disorders using 85,735 cases (33,403 SCZ, 19,924 BIP, and 32,408 MDD) and 109,946 controls from the PGC (Psychiatric Genomics Consortium) and iPSYCH. Results: Across disorders, genome-wide significant single nucleotide polymorphism–by-sex interaction was detected for a locus encompassing NKAIN2 (rs117780815, p = 3.2 × 10−8), which interacts with sodium/potassium-transporting ATPase (adenosine triphosphatase) enzymes, implicating neuronal excitability. Three additional loci showed evidence (p < 1 × 10−6) for cross-disorder G×S interaction (rs7302529, p = 1.6 × 10−7; rs73033497, p = 8.8 × 10−7; rs7914279, p = 6.4 × 10−7), implicating various functions. Gene-based analyses identified G×S interaction across disorders (p = 8.97 × 10−7) with transcriptional inhibitor SLTM. Most significant in SCZ was a MOCOS gene locus (rs11665282, p = 1.5 × 10−7), implicating vascular endothelial cells. Secondary analysis of the PGC-SCZ dataset detected an interaction (rs13265509, p = 1.1 × 10−7) in a locus containing IDO2, a kynurenine pathway enzyme with immunoregulatory functions implicated in SCZ, BIP, and MDD. Pathway enrichment analysis detected significant G×S interaction of genes regulating vascular endothelial growth factor receptor signaling in MDD (false discovery rate-corrected p < .05). Conclusions: In the largest genome-wide G×S analysis of mood and psychotic disorders to date, there was substantial genetic overlap between the sexes. However, significant sex-dependent effects were enriched for genes related to neuronal development and immune and vascular functions across and within SCZ, BIP, and MDD at the variant, gene, and pathway levels. © 2021 Society of Biological Psychiatry
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