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Mood stabilisers plus risperidone or placebo in the treatment of acute mania. International, double-blind, randomised controlled trial.

BACKGROUND: Few double-blind trials have examined the efficacy of a combination of a mood stabiliser and an atypical antipsychotic in acute mania. AIMS: To determine the efficacy of risperidone in combination with a mood stabiliser in acute mania. METHOD: Patients taking a mood stabiliser were randomised to 3 weeks' treatment with risperidone (n=75) or placebo (n=76). RESULTS: Young Mania Rating Scale (YMRS) scores improved rapidly with significantly greater reductions at week 1 in the risperidone group compared with the placebo group. At end-point YMRS scores decreased by 14.5 and 10.3 points in the risperidone and placebo groups, respectively. Significant improvements v. placebo (P<0.05) were noted in the risperidone group on several other clinically meaningful measures. Additionally, a post hoc analysis excluding carbamazepine-treated patients (plasma concentrations of risperidone active moiety were 40% lower in this group) revealed significantly greater reductions (P=0.047) in YMRS scores in the risperidone group than in the placebo group. Incidence of adverse events was similar in both groups. CONCLUSIONS: Risperidone is superior to placebo when used in combination with lithium or divalproex in acute mania.

Adult↗

Cost-effectiveness of clinical interventions for reducing the global burden of bipolar disorder.

BACKGROUND: Bipolar disorder has been ranked seventh among the worldwide causes of non-fatal disease burden. AIMS: To estimate the cost-effectiveness of interventions for reducing the global burden of bipolar disorder. METHOD: Hospital- and community-based delivery of two generic mood stabilisers (lithium and valproic acid), alone and in combination with psychosocial treatment, were modelled for 14 global sub-regions. A population model was employed to estimate the impact of different strategies, relative to no intervention. Total costs (in international dollars (I$)) and effectiveness (disability-adjusted life years (DALYs) averted) were combined to form cost-effectiveness ratios. RESULTS: Baseline results showed lithium to be no more costly yet more effective than valproic acid, assuming an anti-suicidal effect for lithium but not for valproic acid. Community-based treatment with lithium and psychosocial care was most cost-effective (cost per DALY averted: I$2165-6475 in developing sub-regions; I$5487-21123 in developed sub-regions). CONCLUSIONS: Community-based interventions for bipolar disorder were estimated to be more efficient than hospital-based services, each DALY averted costing between one and three times average gross national income.

Adolescent↗

Influence of sub-syndromal symptoms after remission from manic or mixed episodes.

BACKGROUND: Sub-syndromal symptoms in bipolar disorder impair functioning and diminish quality of life. AIMS: To examine factors associated with time spent with sub-syndromal symptoms and to characterise how these symptoms influence outcomes. METHOD: In a double-blind randomised maintenance trial, patients received either olanzapine or lithium monotherapy for 1 year. Stepwise logistic regression models were used to identify factors that were significant predictors of percentage time spent with sub-syndromal symptoms. The presence of sub-syndromal symptoms during the first 8 weeks was examined as a predictor of subsequent relapse. RESULTS: Presence of sub-syndromal depressive symptoms during the first 8 weeks significantly increased the likelihood of depressive relapse (relative risk 4.67, P<0.001). Patients with psychotic features and those with a greater number of previous depressive episodes were more likely to experience sub-syndromal depressive symptoms (RR=2.51, P<0.001 and RR=2.35, P=0.03 respectively). CONCLUSIONS: These findings help to identify patients at increased risk of affective relapse and suggest that appropriate therapeutic interventions should be considered even when syndromal-level symptoms are absent.

Adult↗

Genome-wide methylation biomarkers and biological aging in patients with bipolar disorder characterized for lithium response.

BACKGROUND: Epigenetic mechanisms might play a role in modulating susceptibility to bipolar disorder (BD) and response to lithium, the mainstay treatment for BD. Additionally, individuals with BD experience accelerated biological aging. METHODS: We compared blood DNA methylation profiles measured with EPIC v.2.0 arrays between patients with BD (33 lithium responders and 31 nonresponders) and nonpsychiatric controls (n&#xa0;=&#xa0;32), as well as based on long-term lithium response. In addition, we compared cellular aging between these groups using epigenetic age, pace of aging, and, for the first time, transcriptional age acceleration based on bulk RNA sequencing in 93 patients and 56 controls. RESULTS: We identified 191 differentially methylated positions (DMPs) and 8 differentially methylated regions between patients with BD and controls, located in genes enriched for "Postsynaptic Density" (odds ratio&#xa0;=&#xa0;6.81, p&#xa0;=&#xa0;0.001). No DMP was significantly associated with lithium response after multiple testing correction. Patients showed a significantly higher biological age acceleration than controls based on two epigenetic clocks (GrimAge, Mann-Whitney U&#xa0;=&#xa0;551, p&#xa0;=&#xa0;0.0009; GrimAge2: U&#xa0;=&#xa0;477, p&#xa0;=&#xa0;9.0E-05) and pace of aging (DunedinPACE, t&#xa0;=&#xa0;3.01, p&#xa0;=&#xa0;0.003), but not on transcriptional age. While we observed no significant difference in epigenetic aging based on lithium response, lithium responders showed lower epigenetic acceleration using all clocks, with a trend observed using the PhenoAge clock (t&#xa0;=&#xa0;1.97, p&#xa0;=&#xa0;0.053). CONCLUSIONS: Our findings point to methylation patterns characterizing BD and support the hypothesis of accelerated cellular aging in BD.

Humans↗

Preparation of novel synthons, uniquely functionalized tetrahydrofuran and tetrahydropyran derivatives.

The dianion of the acetoacetic ester reacts with epibromohydrin derivatives to afford a mixture of (Z)-2-alkoxycarbonylmethylidenetetrahydrofuran derivative and (E)-2-alkoxycarbonylmethylidenetetrahydropyran derivative. The selective formation of the tetrahydrofuran derivative is achieved by the use of LiClO4 as the additive. The preparation of the optically active tetrahydrofuran derivatives and tetrahydropyran derivatives is also examined, and the optical purity and absolute configuration of the products is elucidated.

Furans↗

Asymmetric synthesis of a selective endothelin A receptor antagonist.

An asymmetric synthesis of a selective endothelin A receptor antagonist 1b is described. Asymmetric conjugate addition of aryllithium derived from 18 to the chiral oxazoline 17 followed by hydrolysis afforded 15 in 96% ee via purification as (S)-(-)-1-phenylethylamine salt. Pd(OAc)(2)/dppf (1,1'-bis(diphenylphosphino)ferrocene) catalyzed carbonylation followed by chemoselective addition of aryllithium derived from 23 which gave ketone 24. Diastereoselective reduction of the ketone with catecholborane followed by concomitant activation of the resulting alcohol and cyclization gave the late intermediate 26. Introduction of amino moiety on the pyridine ring by imidoyl rearrangement followed by deprotection and purification by crystallization furnished the enantiomerically pure target molecule 1b in 8% overall yield from 16.

Endothelin Receptor Antagonists↗

A chiral ligand-mediated asymmetric addition of a lithium BHA ester enolate to an aldehyde.

The asymmetric reaction of a lithium enolate generated from a BHA (2, 6-di-tert-buty-4-methoxyphenyl) propanoate was allowed to react with benzaldehyde in the presence of a diether-type chiral ligand affording the corresponding anti-aldol product in a moderate enantioselectivity. A tetradentate ligand induced better enantioselectivity albeit relative loss of anti-selectivity. A variation of lithiating amide agent affected the selectivity, indicating involvement of an amine as a component of the mixed aggregate. Absolute configuration of some of the aldol products was determined by standard transformations.

Aldehydes↗

Optimization and deconvolution of lithium fluoride TLD-100 in diagnostic radiology.

Lithium fluoride (LiF) TLD-100 is one of the most commonly used thermoluminescent (TL) materials for the measurement of entrance surface dose (ESD) in diagnostic radiology. However, the minimum detectable dose (MDD) achieved, as derived from measurements of the random uncertainty present in the background signal, is usually quoted as being 50-100 microGy. A more appropriate definition of MDD for use in the clinical setting is the dose at which measurements exhibit a specified level of random uncertainty. This definition will give rise to a higher value for the MDD. An MDD of 50-100 microGy precludes accurate measurement of ESD in high tube potential (kVp) chest or neonatal radiography. Techniques described in the specialist literature for the reduction of the MDD of LiF were assessed both in the laboratory, and during a patient dose survey of high kVp chest radiography. Optimization of the pre-irradiation annealing and post-irradiation TL read heating cycles in terms of sensitivity and precision resulted in an MDD of 5/80 microGy (derived from background signal variation and 20% random uncertainty at 95% confidence limits, respectively). Deconvolution of the glowcurve was found to result in an MDD of approximately 10 microGy. Clinical measurements were contrasted with calculated values derived from ionization chamber measurements of tube output. The results support the hypothesis that glowcurve deconvolution permits the measurement of ESDs from low dose examinations using basic TL dosimetry equipment available to virtually all medical physics departments.

Fluorides↗

Directionality of extruded lithium fluoride thermoluminescent dosemeters in a cobalt-60 beam.

An experimental investigation of the directionality of commercially available extruded lithium fluoride (LiF:Mg,Ti) thermoluminescent dosemeters was carried out in a cobalt-60 beam at a water depth of 5 cm. One-half of a batch of 60 chips (3.1 x 3.1 x 0.9 mm3) was exposed face-on (faces perpendicular to the beam central axis), and the other half was exposed in an edge-on orientation (two edges perpendicular and faces parallel to the beam axis). Measurements show that an edge-on exposure results in a thermoluminescence reading approximately 0.9% lower than a face-on exposure. Although this is of minor importance in every day patient dosimetry, it is relevant in evaluating errors in in-phantom dosimetric measurements where greater accuracy is required.

Calibration↗

The low energy X-ray response of the LiF:Mg:Cu:P thermoluminescent dosemeter: a comparison with LiF:Mg:Ti.

LiF:Mg:Cu:P thermoluminescent dosemeters (TLD) can be used for the same X-ray dosimetry applications as LiF:Mg:Ti, with each type having the disadvantage of a response dependent on energy, particularly at low energies. Measurements were made of the response per unit air kerma of LiF:Mg:Cu:P and LiF:Mg:Ti to nine quasi-monoenergetic X-ray beams with mean energies from 12 keV to 208 keV. Each measurement was normalized to the value produced by 6 MV X-rays. LiF:Mg:Cu:P was found to under-respond to a majority of these radiations whereas LiF:Mg:Ti over-responded to a majority. Their smallest relative measured response was produced by the lowest energy beam, and the maximum measured relative response of 1.15+/-0.07 and 1.21+/-0.07 for LiF:Mg:Cu:P and LiF:Mg:Ti, respectively, occurred at 33 keV. Energy response coefficients were derived from these measurements to estimate the error introduced by using either type of TLD to measure the dose from an X-ray spectrum different to that used for its absolute response calibration. It was calculated that if the response of either type of TLD was calibrated at 100 kVp, then an error of no more than +/-2% would be introduced into measurements of tube output at potentials of 50-130 kVp. LiF:Mg:Cu:P was found to introduce a larger error (up to 30%) into the measurement of body exit dose than LiF:Mg:Ti at tube potentials of 40-150 kVp, if its absolute response was calibrated using the corresponding body entrance beam. The method should allow this type of error to be estimated in other dosimetry applications for either type of TLD.

Copper↗

Separation of cultured strawberry cells producing anthocyanins in aqueous two-phase system.

A rapid and simple selection method of high-yield cells has been desired to establish highly productive cell lines for useful secondary metabolites. For this purpose, a new attempt was made to partition cultured plant cells in a poly(ethylene glycol)-dextran aqueous two-phase system (ATPS). The applicability of the ATPS in partitioning cultured strawberry cells (designated FAW) was investigated. The result of single-step partitioning in the ATPS supplemented with 0.4 mmol/kg lithium sulfate showed that FAW cells cultivated for 7 d under light-irradiation were separated into two cell populations with significantly different anthocyanin content. Additionally, the analysis technique of microscopic cell images showed that cells accumulating a high level of anthocyanin were partitioned completely into the bottom phase in a partitioning experiment of FAW cells cultivated for 10 d under light-irradiation in the ATPS supplemented with 1.8 mmol/kg potassium phosphate buffer. These results indicated that cell partitioning in ATPS increased the intracellular anthocyanin content and that the cultured strawberry cell population was heterogeneous in terms of cell surface properties. This is the first report of partitioning based on the heterogeneity of the cell surface properties correlated with the intracellular secondary metabolism in cultured plant cells. Our results also suggested that the ATPS was appropriate as a large-scale method for selecting useful cell lines among the cultured plant cells.

Anthocyanins↗

Lithium intoxication as a result of an interaction with rofecoxib.

OBJECTIVE: To report the occurrence of lithium intoxication in a patient with bipolar disorder after adding rofecoxib to the medication regimen. CASE SUMMARY: A 68-year-old woman with bipolar disorder under long-term treatment with lithium, carbamazepine, pipamperon, and mirtazapine was prescribed rofecoxib 25 mg twice daily for the treatment of leg pain. Within one week, she showed progressive hypokinesia and tremor, which was treated with propranolol. Subsequently, she developed bradycardia, necessitating treatment with isoproterenol. Her lithium serum concentration had doubled compared with those before rofecoxib, and her renal function had deteriorated. After stopping lithium and rofecoxib, her laboratory values and neurologic signs improved or normalized within 2 days. An objective causality assessment revealed a probable relationship between concomitant use of the drugs and the resulting symptoms. DISCUSSION: As of May 24, 2004, only 3 cases of reversible lithium intoxication as a result of a possible interaction with rofecoxib or celecoxib have been previously reported. The mechanism of the interaction between lithium and cyclooxygenase (COX) 2 selective inhibitors is most probably related to inhibition of renal synthesis of prostaglandins, which are important for the maintenance of renal perfusion and tubular function. Impairment of renal blood flow, leading to a decrease in the glomerular filtration rate, and increased proximal tubular absorption are the most likely mechanisms by which COX-2 selective inhibitors reduce lithium clearance. CONCLUSIONS: Coadministration of rofecoxib and lithium may result in life-threatening lithium intoxication, especially in patients with a preexisting decrease in renal function and/or decreased intravascular volume.

Aged↗

Optical parametric properties of ultraviolet-pumped cesium lithium borate crystals.

We report the optical parametric properties of cesium lithium borate (CLBO) crystals pumped by UV radiation of the fourth-harmonic generation at 266 nm and the third-harmonic generation at 355 nm of a picosecond Nd:YAG laser. A special optical design was used to avoid damage to the optical elements by the UV-pumped beam at 266 nm. The optical parametric generator (OPG)/optical parametric amplifier (OPA) of the 266-nm-pumped CLBO covers the tuning range from 347 nm in the UV to 1137 nm in the near IR. The 355-nm-pumped CLBO OPG/OPA, on the other hand, is tunable from 447 to 1725 nm. The experimental tuning curves for each CLBO OPG/OPA were measured and compared with the theoretical tuning curves. With a double-pass OPG configuration and a pumping intensity of approximately 6 GW/cm2, the maximum conversion efficiency, including both the signal and the idler, was approximately 11% for the 266-nm-pumped CLBO and is greater than 16% for the 355-nm-pumped CLBO without taking into account the surface losses from the uncoated elements. The bandwidth of this double-pass CLBO OPG at various wavelengths was measured and compared with other optical parametric systems. Because of the small angular dispersion of CLBO, the bandwidth of the OPG and OPA systems is exceptionally narrow, especially for the 266-nm-pumped system. Without the use of any dispersion element, the bandwidth of the 266-nm-pumped system can be as narrow as 0.22 nm at wavelengths far from the degenerate point. Comparison between the experimental bandwidth and the theoretical calculation shows that the bandwidth of the UV-pumped CLBO OPG/OPA is limited mainly by the divergence of the pump beam.

Borates↗

Lithium monitoring by reverse iontophoresis in vivo.

BACKGROUND: We investigated reverse transdermal iontophoresis as an alternative, noninvasive method for lithium monitoring in vivo. The objectives of such an approach would be to facilitate compliance with treatment and to improve the quality of life for bipolar patients. METHODS: We studied 23 bipolar or schizo-affective patients. Over a 2-h period, we extracted lithium and other cations across intact skin by application of an electric current (0.8 mA) and quantified the concentrations by ion chromatography. A blood sample provided comparative reference values for the drug and other electrolytes. RESULTS: Lithium, sodium, potassium, and calcium were efficiently extracted by iontophoresis. Lithium extraction fluxes were proportional to the corresponding serum concentrations, whereas sodium, potassium, and calcium extraction fluxes were relatively constant, consistent with their stable concentrations in blood. Normalization of the lithium extraction flux with that of sodium, which acted as an "internal standard", permitted calibration of the monitoring procedure without the need for a blood measurement. This conclusion was tested retrospectively by dividing the patients into two groups. The reverse iontophoretic extraction data from the first subset (a) established the proportionality between lithium iontophoresis (or the relative electrotransport of lithium and sodium) and (b) predicted lithium blood concentrations in the second subset of patients. The predictive ability was very good, with the internal standard concept providing substantial benefit. CONCLUSIONS: Reverse iontophoresis appears to offer a novel and accurate method for lithium monitoring.

Adult↗