[The relationship between intake of lithium and neuroradiological alterations in bipolar disorder. Are there predictors of clinical remission?] / Zusammenhang zwischen der Einnahme von Lithium und neuroradiologischen Veränderungen bei der bipolar affektiven Störung: Gibt es Hinweise auf ein klinisches Ansprechen?

For avoiding affective episodes, patients with bipolar disorders are treated with mood stabilizers. Under that term, the substances lithium, valproic acid, lamotrigine and carbamazepine are included. In the light of upcoming new psychiatric concepts, the use of second generation antipsychotics is also taken into consideration in pharmacological treatment. In this review, the relation between brain structure and the use of lithium in bipolar disorders is examined. Therefore, results from MRI-, DTI-, SPECT-studies assessing this relation, were included.Most of the studies are cross-sectional and examined the effects of lithium. The latter is associated with increased cortical and sub-cortical gray matter volume and ameliorative white matter microstructure. 7-lithium spectroscopy showed a significant difference in brain-lithium concentrations between remitted and non-remitted patients.There are preclinical studies reporting induction of promitotic and antiapoptotic effects by lithium. This literature underpins the hypothesis of lithium-induced neurogenesis. However, osmotic and physical effects of lithium could also explain the demonstrated volume gain in bipolar human brain.Cross-sectional design and small patient groups are typical limitations of numerous studies included in this review.Notably, with the 7-lithium spectroscopy of the central nervous system, new perspectives in clinical research to clarify pharmacokinetic differences between remitted and non-remitted bipolar patients can be established in future.

Psychiatric benefits of lithium in water supplies may be due to protection from the neurotoxicity of lead exposure.

INTRODUCTION: Lithium is a medication used to treat bipolar disorder and may also prevent cognitive decline and suicide. Lithium is also found naturally, in levels well below clinical doses, in drinking water worldwide, and levels have been inversely associated with rates of psychiatric disorders. Lead (Pb) is another element in the environment but is a toxin of public health concern. Negative effects of chronic lead exposure and possible benefits of environmental lithium exposure appear complementary. HYPOTHESIS: Exposure to environmental lithium has associated benefits, which may be due to the mitigation of lead toxicity by lithium. METHODS: A series of reviews tested each element of the hypothesis. A systematic review clarified the psychiatric and medical correlates of lithium in drinking water. Non-systematic reviews clarified the harms of environmental lead, summarized experimental studies of lithium used to prevent lead toxicity, and explored overlapping biological mechanisms in lithium and lead exposure. RESULTS: Higher levels of lithium in drinking water were associated with lower suicide rates in 13 of 15 identified studies. While fewer studies were available for other outcomes, lithium was associated with lower rates of homicide, crime, dementia, and mortality. Lead was reported to be ubiquitous in the environment, and chronic low-level exposure has been associated with adverse effects, including effects opposite to the outcomes associated with lithium. Animal studies demonstrated that lithium pre-treatment mitigates lead toxicity. Neurophysiological correlates of lead and lithium exposure overlap. CONCLUSIONS: Microdose lithium is associated with better psychiatric and medical outcomes, which are complementary to harms of environmental lead exposure. Experimental animal evidence is supportive, and lead and lithium impact overlapping neurophysiologic pathways. Therefore, several lines of circumstantial evidence suggest that lithium protects against the neurotoxic effects of lead. Further studies are required to clarify the benefits and mechanisms of low-dose lithium. There are significant public health implications if this paper's hypothesis is true.

Generation of synthetic influent data to perform (micro)pollutant wastewater treatment modelling studies.

The use of process models to simulate the fate of micropollutants in wastewater treatment plants is constantly growing. However, due to the high workload and cost of measuring campaigns, many simulation studies lack sufficiently long time series representing realistic wastewater influent dynamics. In this paper, the feasibility of the Benchmark Simulation Model No. 2 (BSM2) influent generator is tested to create realistic dynamic influent (micro)pollutant disturbance scenarios. The presented set of models is adjusted to describe the occurrence of three pharmaceutical compounds and one of each of its metabolites with samples taken every 2-4h: the anti-inflammatory drug ibuprofen (IBU), the antibiotic sulfamethoxazole (SMX) and the psychoactive carbamazepine (CMZ). Information about type of excretion and total consumption rates forms the basis for creating the data-defined profiles used to generate the dynamic time series. In addition, the traditional influent characteristics such as flow rate, ammonium, particulate chemical oxygen demand and temperature are also modelled using the same framework with high frequency data. The calibration is performed semi-automatically with two different methods depending on data availability. The 'traditional' variables are calibrated with the Bootstrap method while the pharmaceutical loads are estimated with a least squares approach. The simulation results demonstrate that the BSM2 influent generator can describe the dynamics of both traditional variables and pharmaceuticals. Lastly, the study is complemented with: 1) the generation of longer time series for IBU following the same catchment principles; 2) the study of the impact of in-sewer SMX biotransformation when estimating the average daily load; and, 3) a critical discussion of the results, and the future opportunities of the presented approach balancing model structure/calibration procedure complexity versus predictive capabilities.

Relationships between the psychiatric drug carbamazepine and freshwater macroinvertebrate community structure.

Pharmaceutical pollutants are commonly detected in surface waters and have the potential to affect non-target organisms. However, there is limited understanding of how these emerging contaminants may affect macroinvertebrate communities. The pharmaceutical carbamazepine is ubiquitous in surface waters around the world and is a pollutant of particular concern due to its recalcitrance and toxicity. To better understand the potential effects of carbamazepine on natural macroinvertebrate communities, we related stream macroinvertebrate abundance to carbamazepine concentrations. Macroinvertebrate and water samples were collected from 19 streams in central Indiana in conjunction with other stream physiochemical characteristics. Structural equation modeling (SEM) was used to relate macroinvertebrate richness to carbamazepine concentrations. Macroinvertebrate richness was positively correlated with increasing concentrations of carbamazepine. From the SEM we infer that carbamazepine influences macroinvertebrate richness through indirect pathways linked to Baetidae abundance. Baetidae abundance influenced ephemeropteran abundance and FBOM percent organic matter, both of which altered macroinvertebrate richness. The pharmaceutical carbamazepine may alter freshwater macroinvertebrate species composition, which could have significant consequences to ecosystem processes.

The application of atomic absorption spectrometry for the determination of residual active pharmaceutical ingredients in cleaning validation samples.

The objective of this work was the development and validation of atomic absorption spectrometric (AAS) methods for the determination of residual active pharmaceutical ingredients (API) in rinse samples for cleaning validation. AAS as an indirect method for the determination of API in rinse samples can be applied when it is in the form of salt with metal ions or when the metal ion is a part of the API's structure. The electrothermal AAS methods (aqueous and ethanol medium) for the determination of magnesium in esomeprazole magnesium and the flame AAS method for the determination of lithium in lithium carbonate in rinse samples were developed. Various combinations of solvents were tested and a combination of 1% aqueous or ethanol solution of nitric acid for esomeprazole magnesium and 0.1% aqueous solution of nitric acid for lithium carbonate were found to be the most suitable. The atomization conditions in the graphite furnace and in the flame were carefully studied to avoid losses of analyte and to achieve suitable sensitivity. The cleaning verification methods were validated with respect to accuracy, precision, linearity, limit of detection, and quantification. In all the cases, the limits of detection were at the microgram level. The methods were successfully applied for the determination of esomeprazole magnesium and lithium carbonate in rinse samples from cleaning procedures.

Human health risk assessment of carbamazepine in surface waters of North America and Europe.

A human health risk assessment was carried out for environmental exposures to carbamazepine (CBZ) and its major human metabolites, carbamazepine diol (CBZ-DiOH) and carbamazepine N-glucuronide (CBZ-N-Glu). Carbamazepine is an active pharmaceutical ingredient (API) used worldwide as a medicine for treating epileptic seizures and trigeminal neuralgia. Carbamazepine tends to be detected in surface water more frequently, and at relatively higher concentrations, than most other APIs. Predicted no effect levels (PNECs) for CBZ and its major human metabolites were developed for surface waters to be protective of human health from environmental exposures from drinking water and fish consumption. These PNECs were compared to both measured (MEC) and predicted (PEC) environmental concentrations for North America and Europe. PECs were calculated using the geo-referenced models PhATE for North America and GREAT-ER for Europe. The combined PNEC for drinking water and fish consumption for CBZ is 226,000ng/L. Ninetieth percentile MECs ranged from 150 to 220ng/L, while 90th percentile PECs ranged from 333 to 658ng/L. Calculated margins of safety (MOS) therefore range from 340 to 1500. MOS for the major metabolites are significantly higher. This assessment indicates that CBZ and its major metabolites have high MOS (>>1) and thus should have no appreciable risk to human health through environmental exposures based on available human data.

Efficiency of the Genius batch hemodialysis system with low serum solute concentrations: the case of lithium intoxication therapy.

BACKGROUND: The Genius batch system consists of a 90-L closed reservoir, from which fresh dialysate is extracted at the top and to which spent dialysate is returned at the bottom. It was shown in long-term hemodialysis patients that almost the entire amount of unspent dialysate can be used before contamination of fresh with spent dialysate occurs. Separation is caused by differences in density, partly because of the presence of uremic solutes in spent dialysate. The question is raised whether this separation can be maintained during dialysis of patients who experience an intoxication without renal failure. METHODS: A patient intoxicated with lithium was dialyzed using the Genius system, prepared at 37 degrees C, during 300 minutes. With dialysate flow set at 300 mL/min (5 mL/s) and in the absence of mixing, urea is not expected at the inlet dialysate tubing before minute 300. RESULTS: In the dialysate inlet tubing, an abrupt increase in lithium and urea concentrations was observed 210 minutes after the start of the session, reflecting contamination of fresh with spent dialysate. At minute 210, only 60.9 L of 90 L of dialysate had crossed the dialyzer. In a control dialysis treatment in a patient with marked renal failure, this mixing occurred only at 300 minutes. CONCLUSION: In the present observation, it is shown that during Genius dialysis in a patient without renal failure, an earlier contamination of fresh with spent dialysate can occur, compared to conditions of renal failure.

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.

Region-selective effects of long-term lithium and carbamazepine administration on cyclic AMP levels in rat brain.

The effect of lithium and carbamazepine in the treatment of bipolar affective disorder is well established. Although a number of biochemical effects have been found, the exact molecular mechanisms underlying their therapeutic actions have not been elucidated nor are the target regions in the brain identified. Taken into account the important role of the cyclic AMP second messenger system in the regulation of neuronal exitability and the indications of its involvement in the patophysiology of bipolar affective disorder, we have focused on the drug effects on cyclic AMP levels. The objectives of this investigation were to measure the effects on basal cyclic AMP levels, and to locate target regions within the rat brain after long-term administration of lithium and carbamazepine. Drug treatments were carried out for a period of 28 days. After either drug treatment the cyclic AMP level was increased 3-4 times in frontal cortex but unchanged in hippocampus, hypothalamus, thalamus, amygdala and in cerebellum. In neostriatum the cyclic AMP level was decreased to about 30% after treatment with lithium. We suggest the common region-selective effect, observed for both drugs in frontal cortex, to be essential for the therapeutic actions of lithium and carbamazepine.