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.
OBJECTIVE: Bipolar disorders increase the risk of dementia and show biological and brain alterations, which resemble accelerated aging. Lithium may counter some of these processes and lower the risk of dementia. However, until now no study has specifically investigated the effects of Li on brain age. METHODS: We acquired structural magnetic resonance imaging scans from 84 participants with bipolar disorders (41 with and 43 without Li treatment) and 45 controls. We used a machine learning model trained on an independent sample of 504 controls to estimate the individual brain ages of study participants, and calculated BrainAGE by subtracting chronological from the estimated brain age. RESULTS: BrainAGE was significantly greater in non-Li relative to Li or control participants, F(2, 125) = 10.22, p < 0.001, with no differences between the Li treated and control groups. The estimated brain age was significantly higher than the chronological age in the non-Li (4.28 ± 6.33 years, matched t(42) = 4.43, p < 0.001), but not the Li-treated group (0.48 ± 7.60 years, not significant). Even Li-treated participants with partial prophylactic treatment response showed lower BrainAGE than the non-Li group, F(1, 64) = 4.80, p = 0.03. CONCLUSIONS: Bipolar disorders were associated with greater, whereas Li treatment with lower discrepancy between brain and chronological age. These findings support the neuroprotective effects of Li, which were sufficiently pronounced to affect a complex, multivariate measure of brain structure. The association between Li treatment and BrainAGE was independent of long-term thymoprophylactic response and thus may generalize beyond bipolar disorders, to neurodegenerative disorders.
- MeSH
- bipolární porucha diagnostické zobrazování farmakoterapie MeSH
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- magnetická rezonanční tomografie MeSH
- mozek diagnostické zobrazování patologie MeSH
- multivariační analýza MeSH
- neuroprotektivní látky farmakologie MeSH
- sloučeniny lithia farmakologie MeSH
- strojové učení MeSH
- věkové faktory MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
Regulation of Na+/K+-ATPase in bipolar disorder and lithium therapy has been investigated for more than 40 years. Contradictory results in this area may be caused by the difference between acute and long-term Li effects on cell metabolism and variance in responsiveness of different cell types. We compared the time-course of Li action focusing on Na+/K+-ATPase and lipid peroxidation in two widely different cell models-Jurkat and HEK293. Na+/K+-ATPase expression level was determined in cells cultivated in the absence or presence of 1 mM Li for different time spans (1, 7, and 28 days) using [3H] ouabain binding and immunoblot assay of α-subunit. In parallel samples, the formation of malondialdehyde (MDA) was quantified by HPLC, and 4-hydroxy-2-nonenal (4-HNE) protein adducts were determined by immunoblot. Cultivation of Jurkat cells in 1 mM Li medium resulted in downregulation of Na+/K+-ATPase (decrease of [3H] ouabain-biding sites and intensity of immunoblot signals) in all Li-groups. In HEK293 cells, the decrease of Na+/K+-ATPase was observed after the acute, 1-day exposure only. The long-term treatment with Li resulted in Na+/K+-ATPase upregulation. MDA and 4-HNE modified proteins were decreased in Jurkat cells in all Li-groups. On the other hand, in HEK293 cells, MDA concentration was decreased after the acute, 1-day Li exposure only; the long-term cultivations, for 7 or 28 days, resulted in a significant increase of lipid peroxidation products. The Li-induced decrease of lipid peroxidation products was associated with the decrease of Na+/K+-ATPase level and vice versa.
- MeSH
- bipolární porucha farmakoterapie metabolismus MeSH
- časové faktory MeSH
- HEK293 buňky MeSH
- Jurkat buňky MeSH
- lidé MeSH
- lipidové peroxidy metabolismus MeSH
- peroxidace lipidů účinky léků MeSH
- regulace genové exprese účinky léků MeSH
- sloučeniny lithia aplikace a dávkování metabolismus farmakologie MeSH
- sodíko-draslíková ATPasa genetika metabolismus MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Chronic renal failure (CRF) is associated with an increased incidence of cardiovascular diseases. Intensive research revealed a number of alterations in the heart during CRF; however, possible interventricular differences in CRF-induced cardiac remodeling have so far not been addressed. CRF was induced by two-stage surgical 5/6 nephrectomy (NX) in male Wistar rats. Cellular hypertrophy was quantified using immunohistological morphometric analysis. Contraction force and membrane potential were recorded in left and right ventricle papillary muscles with an isometric force transducer and high-resistance glass microelectrodes. Hypertrophy was present in the left ventricle (LV) of NX animals, but not in the right ventricle (RV) of NX animals, as documented by both ventricle/body weight ratios and cellular morphometric analysis of the cross-sectional area of myocytes. The contraction force was reduced in the LV of NX animals but increased in the RV of NX animals compared with sham-operated rats. Rest potentiation of contraction force was relatively more pronounced in the LV of NX rats. Fifty percent substitution of extracellular sodium with lithium significantly increased the contraction force only in the LV of NX animals. Action potential durations were shortened in both ventricles of CRF animals. Cardiac structural and contractile remodeling in CRF shows significant interventricular differences. CRF induces hypertrophy of the LV but not of the RV. LV hypertrophy was associated with a reduction of contraction force, whereas in the RV, the contraction force was enhanced. Partial recovery of contractile function of the LV by rest potentiation or lithium substitution indicates a role of the Na(+)/Ca(2+) exchanger in this phenomenon.
- MeSH
- chronické selhání ledvin komplikace patofyziologie MeSH
- hypertenze MeSH
- hypertrofie levé komory srdeční komplikace patofyziologie MeSH
- kardiovaskulární nemoci komplikace patofyziologie MeSH
- kontrakce myokardu MeSH
- krysa rodu rattus MeSH
- membránové potenciály MeSH
- náhodné rozdělení MeSH
- nefrektomie MeSH
- potkani Wistar MeSH
- remodelace komor MeSH
- sloučeniny lithia farmakologie MeSH
- srdce - funkce komor MeSH
- srdeční komory patofyziologie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Bipolar disorder is a complex psychiatric condition that has been shown to carry a great degree of genetic loading. This review addresses current research in the genetics of treatment response in bipolar disorder, with a focus on findings that have shaped our understanding of the changing direction of this field in light of recent technological advancements. RECENT FINDINGS: The recent publications in bipolar disorder treatment response have helped consolidate or improve upon knowledge of susceptibility loci and genes in the field. There seems to be an increasing trend toward functionally assessing the role played by putative candidate genes and molecular factors modulating expression in bipolar disorder, as well as a movement toward more global, pathway and genome-wide-oriented research. SUMMARY: Genetic and molecular research to date in bipolar disorder treatment response has not completely answered all the lingering questions in the field, but has contributed to the development of a more patient-based understanding of treatment. In order to apply these findings at a clinical level, more comprehensive treatment response studies are imperative, combining recent advances in high-throughput genomics with functional molecular research.
- MeSH
- antimanika farmakologie MeSH
- bipolární porucha epidemiologie farmakoterapie genetika MeSH
- financování organizované MeSH
- genetická predispozice k nemoci MeSH
- genetická vazba MeSH
- genetické asociační studie MeSH
- lidé MeSH
- regulace genové exprese genetika MeSH
- signální transdukce genetika MeSH
- sloučeniny lithia farmakologie MeSH
- výsledek terapie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
OBJECTIVE: Mitochondrial dysfunctions, impaired bioenergetics and dysfunction of neurotrophins are included in many neurodegenerative and psychiatric diseases. We investigated in vitro effects of pharmacologically different antidepressants and mood stabilizers on mitochondrial enzymes to discover, which mitochondrial functions could be involved in pathophysiology of mood disorders. METHODS: In vitro effects of eight pharmacologically different antidepressants (desipramine, amitriptyline, imipramine, citalopram, venlafaxine, mirtazapine, tianeptine, and moclobemide) and three mood stabilizers (lithium, valproate, and olanzapine) on the activities of mitochondrial enzymes (citrate synthase and enzymes in electron transport chain, i.e. complexes I, II, IV) were measured in crude mitochondrial fraction isolated from pig brain. RESULTS: Most of the antidepressants and mood stabilizers inhibited the activities of respiratory electron transport chain complexes, complexes I and IV were the most affected. Statistically significant decrease of the complex I activity was caused by desipramine, amitriptyline, imipramine, citalopram, mirtazapine, valproate and olanzapine. Complex II was significantly inhibited only by amitriptyline, imipramine, citalopram and venlafaxine. Complex IV was significantly inhibited by all tested drugs except for citalopram and moclobemide. Unchanged or slightly increased citrate synthase activity was observed; significant activation of the enzyme was observed after citalopram, tianeptine and olanzapine. CONCLUSIONS: Our results indicate that antidepressants may act generally as inhibitors of complex I and complex IV of the electron transport chain. These mitochondrial enzymes are suggested as proper candidates in searching of new biological markers of mood disorders, targets of new antidepressants or predictors of response to pharmacotherapy.
- MeSH
- antidepresiva farmakologie MeSH
- antipsychotika farmakologie MeSH
- benzodiazepiny farmakologie MeSH
- citrátsynthasa metabolismus MeSH
- kyselina valproová farmakologie MeSH
- mitochondrie účinky léků MeSH
- mozková kůra účinky léků metabolismus MeSH
- prasata MeSH
- respirační komplex I metabolismus MeSH
- respirační komplex III metabolismus MeSH
- respirační komplex IV metabolismus MeSH
- sloučeniny lithia farmakologie MeSH
- transport elektronů účinky léků MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- srovnávací studie MeSH
- techniky in vitro MeSH
- MeSH
- Alzheimerova nemoc farmakoterapie patologie MeSH
- finanční podpora výzkumu jako téma MeSH
- glykogensynthasa antagonisté a inhibitory fyziologie chemie MeSH
- lithium farmakologie fyziologie terapeutické užití MeSH
- proteiny - lokalizační signály fyziologie genetika MeSH
- sloučeniny lithia farmakologie terapeutické užití MeSH
- Publikační typ
- přehledy MeSH
- srovnávací studie MeSH
- Klíčová slova
- Na+K+Mg++,
- MeSH
- adenosintrifosfatasy farmakologie účinky léků MeSH
- biologické markery MeSH
- biomedicínský výzkum MeSH
- Ca(2+)-Mg(2+)-ATPasa farmakologie účinky léků MeSH
- depresivní poruchy enzymologie farmakoterapie terapie MeSH
- elektrický šok metody využití MeSH
- erytrocytární membrána enzymologie účinky léků MeSH
- experimenty na lidech MeSH
- farmakoterapie MeSH
- lidé MeSH
- sloučeniny lithia farmakologie terapeutické užití MeSH
- sodíko-draslíková ATPasa farmakologie účinky léků MeSH
- statistika jako téma MeSH
- výsledky a postupy - zhodnocení (zdravotní péče) MeSH
- Check Tag
- lidé MeSH
- MeSH
- bipolární porucha farmakoterapie MeSH
- dibenzothiazepiny aplikace a dávkování farmakologie MeSH
- dibenzothiepiny aplikace a dávkování farmakologie MeSH
- haloperidol aplikace a dávkování farmakologie MeSH
- lidé MeSH
- sloučeniny lithia aplikace a dávkování farmakologie MeSH
- výsledek terapie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- srovnávací studie MeSH
