Lithium response
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Jak je lithium používáno v ČR, jaké mají psychiatři praktické zkušenosti s lithiem a názory na jeho používání, se pokusil zjistit dotazník, který byl distribuován na neuropsychofarmakologické konferenci.
The purpose of the questionnaire distributed on the neuropsychopharmacologic conference was to establish the situation of lithium use in the Czech Republic, such as psychiatrist‘s experiences with lithium and their views about it.
Importance: 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). Objectives: 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. Design, Setting, and Participants: 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 36 989 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. Main Outcomes and Measures: 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. Results: 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. Conclusions and Relevance: 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.
- MeSH
- bipolární porucha farmakoterapie genetika MeSH
- celogenomová asociační studie * MeSH
- dospělí MeSH
- genetická zátěž MeSH
- genotyp MeSH
- HLA antigeny genetika MeSH
- lidé středního věku MeSH
- lidé MeSH
- lithiumkarbonát terapeutické užití MeSH
- multifaktoriální dědičnost genetika MeSH
- schizofrenie (psychologie) MeSH
- schizofrenie farmakoterapie genetika MeSH
- výsledek terapie MeSH
- zánět genetika MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- randomizované kontrolované studie MeSH
- Research Support, N.I.H., Extramural MeSH
Psychiatrický výzkum je limitován řadou faktorů, mezi nimiž podstatnou roli hraje diagnóza. Validita psychiatrických diagnóz je zpochybnéna jednak tím, že neznáme patofyziologii duševních nemocí, jednak absencí diagnostických testů. Robins a Guze (1970) navrhli pět kritérií k validizaci psychiatrických diagnostických kategorií. V tomto přehledu shrnuji data, která ukazují, že bipolární porucha s kompletní odpovědí na léčbu lithiem splňuje kriteria Robinse a Guzeho. Tito pacienti 1) mají specifický klinický obraz, 2) liší se od respondérů na jiné typy dlouhodobé léčby; 3) odpověď na lithium je dlouhodobě stabilní, 4) má charakteristický genetický profil a 5) koreluje s určitými biologickými markery. Vzhledem k těmto vlastnostem jsou lithioví respondéři vhodnou populací pro výzkum etiologických faktorů u poruch nálady.
Accurate diagnosis is prominent among the factors limiting psychiatric research. Validity of psychiatric diagnosis is problematic in light of unknown pathophysiology and non-existent diagnostic tests. Robins and Guze (1970) proposed five criteria that should aid in defining a valid psychiatric diagnosis. In this paper I show that bipolar disorder responsive to lithium meets the Robins and Guze criteria by being 1) clinically distinct, 2) different from the forms of bipolar disorder responsive to other long term treatments, 3) longitudinally stable, 4) familial, and 5) likely associated with specific biological markers. These properties make bipolar disorder responsive to lithium particularly promising in search for etiological factors in mood disorders.
- MeSH
- bipolární porucha diagnóza genetika klasifikace MeSH
- farmakogenetika metody MeSH
- genetická predispozice k nemoci klasifikace prevence a kontrola MeSH
- lidé MeSH
- lithium aplikace a dávkování farmakokinetika MeSH
- následné studie MeSH
- psychopatologie klasifikace MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- Check Tag
- lidé MeSH
Mezi faktory, které mohou ovlivňovat účinky léčiv, patří současné podávání jiných farmak. Způsobů, kterými spolu léky mohou vzájemně interagovat je několik, ale nejčastěji se lékové interakce dělí na farmakokinetické (absorpce, distribuce, metabolizmus, exkrece), farmakodynamické nebo na smíšené. Znalost mechanizmů, kterými nějaká interakce probíhá je důležitá v praxi, neboť při znalosti mechanizmu interakce můžeme ovlivnit její průběh nebo se jí někdy zcela záměrně můžeme vyhnout. Některé důležité interakce mezi léčivy se odehrávají na úrovni dvou či více mechanizmů. Tabulka lékových interakcí antidepresiv a lithia je rozdělena do následujících částí: nejprve jsou uvedeny interagující léčiva, výsledek lékové interakce a její mechanizmus, klinická závažnost a dokumentace vážící se k dané interakci. Jestliže hodnotíme nějakou potenciální lékovou interakci zaměřujeme se na její klinický význam a závažnost. Potenciálně závažná léková interakce je zvláště důležitá z hlediska hodnocení risku a benefitu terapeutických možností. Při vhodné úpravě dávkování nebo úpravě režimu, můžeme řadě negativních účinků většiny interakcí předejít. V tabulce jsou uvedeny 4 stupně závažnosti interakcí, označené písmeny A-D. Úroveň dokumentace je označena čísly 1-4.
One of the factors that can alter the response to drug is the concurrent administration of other drugs. There are several mechanisms by which drugs may interact, but most can be categorized as pharmacokinetic (absorption, distribution, metabolism, excretion), pharmacodnamic or combined interaction. Knowledge of the mechanism by which a given drug interaction occurs is often clinically useful, since the mechanism may influence both the time course and the methods of circumventing the interaction. Some important drug interactions occur as a result of two or more mechanisms. The table of antidepressant and lithium drug interaction of antidepressant drugs and lithuim listed below is divided into the following sections: interacting drugs, outcome and mechanism of the interaction, clinical relevance and documentation of the interaction. When evaluating any potential drug ineraction, a primary concern is the clinical relevance or significance of the interaction. The potential severity of the interaction is particularly important in assessing the risk vs benefit of therapeutic alternatives. With appropriate dosage adjustments or modification of the administration schedule, the negative effects of most interactions can be avoided. In the table there are four degree of relevance of interaction and they are defined by letters A-D. Documentation levels are marked of numbers 1-4.
Telomeres consist of exanucleotide tandem repeats and proteins complexes at the end of chromosome ends. Telomeres shorten at each cell division, and as such telomere length is a marker of cellular age. Accelerated telomere shortening and cell senescence have been associated with a number of chronic medical conditions, including psychiatric disorders, where increased prevalence of age-related disorders and shorter telomere length have been reported. Shorter telomeres in psychiatric patients are thought to be the consequence of allostatic load, consisting in the overactivation of allostatic systems due to chronic exposure to severe medical conditions and failure to adapt to chronic stressful stimuli. Most of the studies on telomere length in psychiatry have focused on major depressive disorder, but recent findings have shown shorter leukocyte telomere length in bipolar disorder patients and suggested that lithium may counteract telomeres shortening. These findings provided new insights into the pathophysiology of bipolar disorder and the mechanism of action of lithium. In this review we will present findings from the literature on telomere length in bipolar disorder, with a specific focus on lithium. We will also discuss advances and limitations of published work as well as methodological issues and potential confounding factors that should be taken into account when designing research protocols to study telomere length.
- MeSH
- bipolární porucha krev diagnóza farmakoterapie MeSH
- homeostáza telomer účinky léků fyziologie MeSH
- lidé MeSH
- lithium farmakologie terapeutické užití MeSH
- telomery účinky léků fyziologie MeSH
- výsledek terapie MeSH
- zkracování telomer účinky léků fyziologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
BACKGROUND: Lithium is regarded as a first-line treatment for bipolar disorder (BD), but partial response and non-response commonly occurs. There exists a need to identify lithium non-responders prior to initiating treatment. The Pharmacogenomics of Bipolar Disorder (PGBD) Study was designed to identify predictors of lithium response. METHODS: The PGBD Study was an eleven site prospective trial of lithium treatment in bipolar I disorder. Subjects were stabilized on lithium monotherapy over 4 months and gradually discontinued from all other psychotropic medications. After ensuring a sustained clinical remission (defined by a score of ≤3 on the CGI for 4 weeks) had been achieved, subjects were followed for up to 2 years to monitor clinical response. Cox proportional hazard models were used to examine the relationship between clinical measures and time until failure to remit or relapse. RESULTS: A total of 345 individuals were enrolled into the study and included in the analysis. Of these, 101 subjects failed to remit or relapsed, 88 achieved remission and continued to study completion, and 156 were terminated from the study for other reasons. Significant clinical predictors of treatment failure (p < 0.05) included baseline anxiety symptoms, functional impairments, negative life events and lifetime clinical features such as a history of migraine, suicidal ideation/attempts, and mixed episodes, as well as a chronic course of illness. CONCLUSIONS: In this PGBD Study of lithium response, several clinical features were found to be associated with failure to respond to lithium. Future validation is needed to confirm these clinical predictors of treatment failure and their use clinically to distinguish who will do well on lithium before starting pharmacotherapy.
- MeSH
- bipolární porucha * diagnóza farmakoterapie genetika MeSH
- farmakogenetika MeSH
- lidé MeSH
- lithium terapeutické užití MeSH
- prospektivní studie MeSH
- sloučeniny lithia terapeutické užití MeSH
- výsledek terapie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky MeSH
- multicentrická studie MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
- Research Support, U.S. Gov't, Non-P.H.S. MeSH
OBJECTIVES: The Retrospective Assessment of the Lithium Response Phenotype Scale (Alda scale) is the most widely used clinical measure of lithium response phenotypes. We assess its performance against recommended psychometric and clinimetric standards. METHODS: We used data from the Consortium for Lithium Genetics and a French study of lithium response phenotypes (combined sample >2500) to assess reproducibility, responsiveness, validity, and interpretability of the A scale (assessing change in illness activity), the B scale, and its items (assessing confounders of response) and the previously established response categories derived from the Total Score for the Alda scale. RESULTS: The key findings are that the B scale is vulnerable to error measurement. For example, some items contribute little to overall performance of the Alda scale (eg, B2) and that the B scale does not reliably assess a single construct (uncertainty in response). Machine learning models indicate that it may be more useful to employ an algorithm for combining the ratings of individual B items in a sequence that clarifies the noise to signal ratio instead of using a composite score. CONCLUSIONS: This study highlights three important topics. First, empirical approaches can help determine which aspects of the performance of any scale can be improved. Second, the B scale of the Alda is best applied as a multidimensional index (identifying several independent confounders of the assessment of response). Third, an integrated science approach to precision psychiatry is vital, otherwise phenotypic misclassifications will undermine the reliability and validity of findings from genetics and biomarker studies.
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.
- MeSH
- bipolární porucha * farmakoterapie genetika MeSH
- celogenomová asociační studie MeSH
- fokální adheze MeSH
- fosfatidylinositol-3-kinasy genetika MeSH
- lidé MeSH
- lithium * farmakologie terapeutické užití MeSH
- multiomika MeSH
- protoonkogenní proteiny c-akt genetika MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
