Tardive Dystonia due to D2 Antagonists and Other Agents

Tardive dystonia due to D2 antagonists or other agents is a potentially severe extrapyramidal side effect emerging after long-term drug treatment, prevalent but not limited to psychiatric populations. Its course is often deteriorating, and available treatments are frequently far from satisfying. It presents with sustained muscle contractions, abnormal postures, and repetitive twisting movements and leads to increased psychiatric morbidity, mortality, and decline of quality of life. Inadequate clinical skill and awareness of tardive dystonia can lead to neglect or misdiagnoses, considered as conversion symptoms or of psychogenic origin. Since the syndrome is persistent and often treatment resistant, prevention should be a mainstay of clinical care. Emerging evidence supports positive effects of atypical antipsychotics, particularly quetiapine and clozapine. Therapies such as tetrabenazine, valbenazine, deutetrabenazine, anticholinergics, baclofen, benzodiazepines, vitamin E, or non-pharmacologic interventions, namely botulinum toxin A, deep-brain stimulation, have been found to be helpful in some cases of tardive dystonia. This chapter comprehensively illustrates multiple aspects of this entity, including recent advances on etiology, pathophysiology, clinical presentation, epidemiology, pharmacogenomics, and treatment, aiming to enhance and deepen clinicians’ and researchers’ awareness of tardive dystonia, with the final goal of ameliorating patients’ prognosis and quality of life

Integrating Next-Generation Sequencing in the Clinical Pharmacogenomics Workflow

Pharmacogenomics has been recognized as a fundamental tool in the era of personalized medicine with up to 266 drug labels, approved by major regulatory bodies, currently containing pharmacogenomics information. Next-generation sequencing analysis assumes a critical role in personalized medicine, providing a comprehensive profile of an individual’s variome, particularly that of clinical relevance, comprising of pathogenic variants and pharmacogenomic biomarkers. Here, we propose a strategy to integrate next-generation sequencing into the current clinical pharmacogenomics workflow from deep resequencing to pharmacogenomics consultation, according to the existing guidelines and recommendations

Documentation of clinically relevant genomic biomarker allele frequencies in the next-generation FINDbase worldwide database

FINDbase (http://www.findbase.org) is a comprehensive data resource recording the prevalence of clinically relevant genomic variants in various populations worldwide, such as pathogenic variants underlying genetic disorders as well as pharmacogenomic biomarkers that can guide drug treatment. Here, we report significant new developments and technological advancements in the database architecture, leading to a completely revamped database structure, querying interface, accompanied with substantial extensions of data content and curation. In particular, the FINDbase upgrade further improves the user experience by introducing responsive features that support a wide variety of mobile and stationary devices, while enhancing computational runtime due to the use of a modern Javascript framework such as ReactJS. Data collection is significantly enriched, with the data records being divided in a Public and Private version, the latter being accessed on the basis of data contribution, according to the microattribution approach, while the front end was redesigned to support the new functionalities and querying tools. The abovementioned updates further enhance the impact of FINDbase, improve the overall user experience, facilitate further data sharing by microattribution, and strengthen the role of FINDbase as a key resource for personalized medicine applications and personalized public health

Genomic variants in the FTO gene are associated with sporadic amyotrophic lateral sclerosis in Greek patients

Background: Amyotrophic lateral sclerosis (ALS) is a devastating disease whose complex pathology has been associated with a strong genetic component in the context of both familial and sporadic disease. Herein, we adopted a next-generation sequencing approach to Greek patients suffering from sporadic ALS (together with their healthy counterparts) in order to explore further the genetic basis of sporadic ALS (sALS). Results: Whole-genome sequencing analysis of Greek sALS patients revealed a positive association between FTO and TBC1D1 gene variants and sALS. Further, linkage disequilibrium analyses were suggestive of a specific diseaseassociated haplotype for FTO gene variants. Genotyping for these variants was performed in Greek, Sardinian, and Turkish sALS patients. A lack of association between FTO and TBC1D1 variants and sALS in patients of Sardinian and Turkish descent may suggest a founder effect in the Greek population. FTO was found to be highly expressed in motor neurons, while in silico analyses predicted an impact on FTO and TBC1D1 mRNA splicing for the genomic variants in question. Conclusions: To our knowledge, this is the first study to present a possible association between FTO gene variants and the genetic etiology of sALS. In addition, the next-generation sequencing-based genomics approach coupled with the two-step validation strategy described herein has the potential to be applied to other types of human complex genetic disorders in order to identify variants of clinical significance

Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors

Background Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. Methods We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. Results Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. Conclusions Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.Peer reviewe

Global, regional, and national burden of disorders affecting the nervous system, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

BackgroundDisorders affecting the nervous system are diverse and include neurodevelopmental disorders, late-life neurodegeneration, and newly emergent conditions, such as cognitive impairment following COVID-19. Previous publications from the Global Burden of Disease, Injuries, and Risk Factor Study estimated the burden of 15 neurological conditions in 2015 and 2016, but these analyses did not include neurodevelopmental disorders, as defined by the International Classification of Diseases (ICD)-11, or a subset of cases of congenital, neonatal, and infectious conditions that cause neurological damage. Here, we estimate nervous system health loss caused by 37 unique conditions and their associated risk factors globally, regionally, and nationally from 1990 to 2021.MethodsWe estimated mortality, prevalence, years lived with disability (YLDs), years of life lost (YLLs), and disability-adjusted life-years (DALYs), with corresponding 95% uncertainty intervals (UIs), by age and sex in 204 countries and territories, from 1990 to 2021. We included morbidity and deaths due to neurological conditions, for which health loss is directly due to damage to the CNS or peripheral nervous system. We also isolated neurological health loss from conditions for which nervous system morbidity is a consequence, but not the primary feature, including a subset of congenital conditions (ie, chromosomal anomalies and congenital birth defects), neonatal conditions (ie, jaundice, preterm birth, and sepsis), infectious diseases (ie, COVID-19, cystic echinococcosis, malaria, syphilis, and Zika virus disease), and diabetic neuropathy. By conducting a sequela-level analysis of the health outcomes for these conditions, only cases where nervous system damage occurred were included, and YLDs were recalculated to isolate the non-fatal burden directly attributable to nervous system health loss. A comorbidity correction was used to calculate total prevalence of all conditions that affect the nervous system combined.FindingsGlobally, the 37 conditions affecting the nervous system were collectively ranked as the leading group cause of DALYs in 2021 (443 million, 95% UI 378–521), affecting 3·40 billion (3·20–3·62) individuals (43·1%, 40·5–45·9 of the global population); global DALY counts attributed to these conditions increased by 18·2% (8·7–26·7) between 1990 and 2021. Age-standardised rates of deaths per 100 000 people attributed to these conditions decreased from 1990 to 2021 by 33·6% (27·6–38·8), and age-standardised rates of DALYs attributed to these conditions decreased by 27·0% (21·5–32·4). Age-standardised prevalence was almost stable, with a change of 1·5% (0·7–2·4). The ten conditions with the highest age-standardised DALYs in 2021 were stroke, neonatal encephalopathy, migraine, Alzheimer's disease and other dementias, diabetic neuropathy, meningitis, epilepsy, neurological complications due to preterm birth, autism spectrum disorder, and nervous system cancer.InterpretationAs the leading cause of overall disease burden in the world, with increasing global DALY counts, effective prevention, treatment, and rehabilitation strategies for disorders affecting the nervous system are needed

Global burden of 288 causes of death and life expectancy decomposition in 204 countries and territories and 811 subnational locations, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

BACKGROUND Regular, detailed reporting on population health by underlying cause of death is fundamental for public health decision making. Cause-specific estimates of mortality and the subsequent effects on life expectancy worldwide are valuable metrics to gauge progress in reducing mortality rates. These estimates are particularly important following large-scale mortality spikes, such as the COVID-19 pandemic. When systematically analysed, mortality rates and life expectancy allow comparisons of the consequences of causes of death globally and over time, providing a nuanced understanding of the effect of these causes on global populations. METHODS The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 cause-of-death analysis estimated mortality and years of life lost (YLLs) from 288 causes of death by age-sex-location-year in 204 countries and territories and 811 subnational locations for each year from 1990 until 2021. The analysis used 56 604 data sources, including data from vital registration and verbal autopsy as well as surveys, censuses, surveillance systems, and cancer registries, among others. As with previous GBD rounds, cause-specific death rates for most causes were estimated using the Cause of Death Ensemble model-a modelling tool developed for GBD to assess the out-of-sample predictive validity of different statistical models and covariate permutations and combine those results to produce cause-specific mortality estimates-with alternative strategies adapted to model causes with insufficient data, substantial changes in reporting over the study period, or unusual epidemiology. YLLs were computed as the product of the number of deaths for each cause-age-sex-location-year and the standard life expectancy at each age. As part of the modelling process, uncertainty intervals (UIs) were generated using the 2·5th and 97·5th percentiles from a 1000-draw distribution for each metric. We decomposed life expectancy by cause of death, location, and year to show cause-specific effects on life expectancy from 1990 to 2021. We also used the coefficient of variation and the fraction of population affected by 90% of deaths to highlight concentrations of mortality. Findings are reported in counts and age-standardised rates. Methodological improvements for cause-of-death estimates in GBD 2021 include the expansion of under-5-years age group to include four new age groups, enhanced methods to account for stochastic variation of sparse data, and the inclusion of COVID-19 and other pandemic-related mortality-which includes excess mortality associated with the pandemic, excluding COVID-19, lower respiratory infections, measles, malaria, and pertussis. For this analysis, 199 new country-years of vital registration cause-of-death data, 5 country-years of surveillance data, 21 country-years of verbal autopsy data, and 94 country-years of other data types were added to those used in previous GBD rounds. FINDINGS The leading causes of age-standardised deaths globally were the same in 2019 as they were in 1990; in descending order, these were, ischaemic heart disease, stroke, chronic obstructive pulmonary disease, and lower respiratory infections. In 2021, however, COVID-19 replaced stroke as the second-leading age-standardised cause of death, with 94·0 deaths (95% UI 89·2-100·0) per 100 000 population. The COVID-19 pandemic shifted the rankings of the leading five causes, lowering stroke to the third-leading and chronic obstructive pulmonary disease to the fourth-leading position. In 2021, the highest age-standardised death rates from COVID-19 occurred in sub-Saharan Africa (271·0 deaths [250·1-290·7] per 100 000 population) and Latin America and the Caribbean (195·4 deaths [182·1-211·4] per 100 000 population). The lowest age-standardised death rates from COVID-19 were in the high-income super-region (48·1 deaths [47·4-48·8] per 100 000 population) and southeast Asia, east Asia, and Oceania (23·2 deaths [16·3-37·2] per 100 000 population). Globally, life expectancy steadily improved between 1990 and 2019 for 18 of the 22 investigated causes. Decomposition of global and regional life expectancy showed the positive effect that reductions in deaths from enteric infections, lower respiratory infections, stroke, and neonatal deaths, among others have contributed to improved survival over the study period. However, a net reduction of 1·6 years occurred in global life expectancy between 2019 and 2021, primarily due to increased death rates from COVID-19 and other pandemic-related mortality. Life expectancy was highly variable between super-regions over the study period, with southeast Asia, east Asia, and Oceania gaining 8·3 years (6·7-9·9) overall, while having the smallest reduction in life expectancy due to COVID-19 (0·4 years). The largest reduction in life expectancy due to COVID-19 occurred in Latin America and the Caribbean (3·6 years). Additionally, 53 of the 288 causes of death were highly concentrated in locations with less than 50% of the global population as of 2021, and these causes of death became progressively more concentrated since 1990, when only 44 causes showed this pattern. The concentration phenomenon is discussed heuristically with respect to enteric and lower respiratory infections, malaria, HIV/AIDS, neonatal disorders, tuberculosis, and measles. INTERPRETATION Long-standing gains in life expectancy and reductions in many of the leading causes of death have been disrupted by the COVID-19 pandemic, the adverse effects of which were spread unevenly among populations. Despite the pandemic, there has been continued progress in combatting several notable causes of death, leading to improved global life expectancy over the study period. Each of the seven GBD super-regions showed an overall improvement from 1990 and 2021, obscuring the negative effect in the years of the pandemic. Additionally, our findings regarding regional variation in causes of death driving increases in life expectancy hold clear policy utility. Analyses of shifting mortality trends reveal that several causes, once widespread globally, are now increasingly concentrated geographically. These changes in mortality concentration, alongside further investigation of changing risks, interventions, and relevant policy, present an important opportunity to deepen our understanding of mortality-reduction strategies. Examining patterns in mortality concentration might reveal areas where successful public health interventions have been implemented. Translating these successes to locations where certain causes of death remain entrenched can inform policies that work to improve life expectancy for people everywhere. FUNDING Bill & Melinda Gates Foundation

Pharmacogenomics in individualizing treatment of schizophrenic and emotional psychosis

Schizophrenia is the most serious psychiatric disorder that affects about 1% of people worldwide and so far, its etiology is still unknown. In this study, we first conducted a systematic literature survey of articles investigating a possible association between genetic variants in candidate genes and the variable treatment response of schizophrenia patients under risperidone and clozapine treatment. Forty-nine studies, involving 6,786 controls and 5,705 patients with schizophrenia of Caucasian, Han Chinese, Japanese, Korean and Afro-American origin, were collected and meta-analyzed. Our meta-analysis revealed that the two SNPs, rs6313 and rs1799978 found in HTR2A and DRD2 receptor genes respectively were associated with clozapine treatment efficacy. To confirm these findings, we genotyped 413 SZ cases and 340 controls of Greek, Slovenian and Croatian descent for those variants, using PCR-RFLP, Sanger Sequencing, and SimpleProbe Analysis. Our data show that rs6313 is associated with patients’ response to atypical antipsychotics. Overall, our findings suggest that rs6313 can be potentially useful as a pharmacogenomic biomarker for risperidone and clozapine treatment of SZ patients.Bipolar disorder is a severe psychiatric disorder affecting 1% to 3% of the general population. Lithium is the first line therapy for long term management of BD, being effective in preventing depression and mania and reducing the risk of suicide. Studies have shown that the use of Li+ in clinical psychiatry may be associated with a reduction of eGFR in patients with long-term Li+ treatment. The aim of our study was to identify genetic variants associated with Li+-induced eGFR in a sample of Sardinian bipolar patients under long-term Li+ treatment. For this reason, tag SNPs from genes previously shown to be associated with kidney dysfunction or Li+ metabolism were selected and genotyped using the Invader assay and Sanger sequencing. According to our results, rs378448, located in ACCN1 (or ASIC2) gene, previously shown by our group to be associated with Li+ treatment response in bipolar disease patients, was significantly associated with Li+-induced reduction of eGFR, while statistical significance remained after adjustment of pvalue for variables like age, gender, smoking habits and years or Li treatment. In conclusion, our findings provide preliminary evidence that rs378448 may constitute potential predictor for a better use of Li and increase safety in treatment of bipolar patients.Η σχιζοφρένεια είναι η σοβαρότερη ψυχιατρική διαταραχή που επηρεάζει περίπου το 1% του πληθυσμού παγκοσμίως και μέχρι σήμερα η αιτιολογία της δεν είναι γνωστή. Στην παρούσα διατριβή, πραγματοποιήθηκε αρχικά βιβλιογραφική ανασκόπηση των άρθρων που μελετούσαν γενετικές αλλαγές υποψήφιων γονιδίων και την πιθανή συσχέτιση τους με τη θεραπεία της σχιζοφρένειας, συγκεκριμένα με τη ρισπεριδόνη και την κλοζαπίνη. Συγκεντρώθηκαν συνολικά, 49 μελέτες, οι οποίες αφορούσαν 6.786 δείγματα αναφοράς και 5.705 ασθενείς με σχιζοφρένεια, Καυκάσιας, Κινέζικης Χαν, Ιαπωνικής, Κορεατικής και Αφρο-αμερικανικής προέλευσης. Στη συνέχεια, έγινε μετα-ανάλυση των δεδομένων αυτών και βρέθηκε ότι δύο γενετικές αλλαγές, ο rs6313 και ο rs1799978, που βρίσκονται στα γονίδια HTR2A και DRD2, αντίστοιχα, πιθανόν να σχετίζονται με την αποτελεσματικότητα στην αντιψυχωτική θεραπεία. Τέλος, έγινε προσπάθεια επιβεβαίωσης των αποτελεσμάτων της μετα-ανάλυσης σε δείγμα Καυκάσιων ασθενών που συμπεριλάμβανε 413 ασθενείς με σχιζοφρένεια και 340 υγιή άτομα ελληνικής, σλοβένικης και κροατικής προέλευσης, με τις μεθόδους RFLP, Sanger Sequencing και SimpleProbe Analysis. Η ανάλυση κατέδειξε πιθανή συσχέτιση του rs6313 με την ανταπόκριση των ασθενών στα άτυπα αντιψυχωσικά στον ελληνικό πληθυσμό. Συμπερασματικά, τα ευρήματά μας υποδηλώνουν ότι το rs6313 μπορεί πιθανόν να χρησιμοποιηθεί ως φαρμακογονιδιωματικός βιοδείκτης για τη θεραπεία των ασθενών με σχιζοφρένεια.Η διπολική διαταραχή είναι μια σοβαρή ψυχιατρική διαταραχή που επηρεάζει το 1% έως 3% του γενικού πληθυσμού. Το λίθιο είναι η θεραπεία πρώτης γραμμής για τη νόσο, καθώς είναι αποτελεσματικό, τόσο στην πρόληψη της κατάθλιψης και της μανίας, αλλά και στην μείωση του κινδύνου αυτοκτονίας. Μελέτες έχουν δείξει ότι η χρήση του μπορεί να σχετίζεται με μείωση του eGFR σε ασθενείς υπό μακροχρόνια χορήγηση λιθίου. Σκοπός της μελέτης μας ήταν ο προσδιορισμός γενετικών αλλαγών που σχετίζονται με την μείωση του eGFR που επάγεται από το λίθιο σε διπολικούς Σαρδήνιους ασθενείς υπό μακροχρόνια χορήγηση λιθίου. Για το λόγο αυτό, επιλέχθηκαν SNPs επισήμανσης (tag SNPs) υποψήφιων γονιδίων που έχει προηγουμένως δειχθεί ότι σχετίζονται είτε με την δυσλειτουργία των νεφρών είτε με τον μεταβολισμό του λιθίου και γονοτυπήθηκαν με την μέθοδο αλληλούχιση κατά Sanger ή την μέθοδο Invader, η οποία βασίζεται στην ανίχνευση ενός φθορίζοντος σήματος, που προκύπτει από την διάσπαση ενός τρισδιάστατου συμπλόκου, μεταξύ επικαλυπτόμενων ολιγονουκλεοτιδίων και της αλληλουχίας στόχο. Σύμφωνα με τα αποτελέσματά, ο rs378448, που βρίσκεται στο γονίδιο ACCN1 (ή ASIC2), το οποίο είχε δειχθεί στο παρελθόν από την ερευνητική μας ομάδα να σχετίζεται με την ανταπόκριση σε λίθιο μανιοκαταθλιπτικών ασθενών, εμφάνισε στατιστική σημαντικότητα (pvalue=0.0287), η οποία συνέχισε να υπάρχει ακόμα και μετά την προσαρμογή του pvalue για μεταβλητές όπως η ηλικία, το φύλο, οι συνήθειες καπνίσματος και χρόνια θεραπεία με λίθιο, παρέχοντας ενδείξεις ότι θα μπορούσε ενδεχομένως να εμπλέκεται στην μείωση του eGFR, που επάγεται από το λίθιο. Τα ευρήματά μας παρέχουν προκαταρκτικές ενδείξεις που εάν επιβεβαιωθούν, μπορεί να αποτελέσουν πιθανούς παράγοντες πρόβλεψης για την καλύτερη χρήση του λιθίου και να οδηγήσουν στην ασφαλέστερη θεραπεία των διπολικών ασθενών

Alcohol-induced oxidative stress and the role of antioxidants in alcohol use disorder: a systematic review.

Alcohol use disorder (AUD) is a highly prevalent, comorbid, and disabling disorder. The underlying mechanism of ethanol neurotoxicity and the involvement of oxidative stress is still not fully elucidated. However, ethanol metabolism has been associated with increased oxidative stress through alcohol dehydrogenase, the microsomal ethanol oxidation system, and catalase metabolic pathways. We searched the PubMed and genome-wide association studies (GWAS) catalog databases to review the literature systematically and summarized the findings focusing on AUD and alcohol abstinence in relation to oxidative stress. In addition, we reviewed the ClinicalTrials.gov resource of the US National Library of Medicine to identify all ongoing and completed clinical trials that include therapeutic interventions based on antioxidants. The retrieved clinical and preclinical studies show that oxidative stress impacts AUD through genetics, alcohol metabolism, inflammation, and neurodegeneration

Psychiatric Genomics

Psychiatric Genomics presents and synthesizes available knowledge in the field of psychiatric genomics, offering methodologies to advance new research and aid clinical translation. After providing an introduction to genomics and psychiatry, international experts discuss the genomic basis of schizophrenia, bipolar disorder, depression, personality disorders, anxiety disorders, addictions, eating disorders, and sleep disorders, among other disorders. In addition, recommendations for next steps in clinical implementation and drug discovery are discussed in-depth, with chapters dedicated to pharmacogenomics and antipsychotics, antidepressants and mood stabilizers, adverse drug reactions, implementation of pharmacogenomics in psychiatric clinics, and ethical issues. Finally, methods sections provide a solid grounding in research approaches and computational analytics, from using animal models in psychiatric genomics and accessing biobanks, to employing computational analysis, genome-wide association studies (GWAS), brain pathophysiology, and endophenotypes in psychiatric research