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Background: Lithium (Li) remains the treatment of choice for bipolar disorders (BP). Its mood-stabilizing effects help reduce the long-term burden of mania, depression and suicide risk in patients with BP. It also has been shown to have beneficial effects on disease-associated conditions, including sleep and cardiovascular disorders. However, the individual responses to Li treatment vary within and between diagnostic subtypes of BP (e.g. BP-I and BP-II) according to the clinical presentation. Moreover, long-term Li treatment has been linked to adverse side-effects that are a cause of concern and non-adherence, including the risk of developing chronic medical conditions such as thyroid and renal disease. In recent years, studies by the Consortium on Lithium Genetics (ConLiGen) have uncovered a number of genetic factors that contribute to the variability in Li treatment response in patients with BP. Here, we leveraged the ConLiGen cohort (N = 2064) to investigate the genetic basis of Li effects in BP. For this, we studied how Li response and linked genes associate with the psychiatric symptoms and polygenic load for medical comorbidities, placing particular emphasis on identifying differences between BP-I and BP-II. Results: We found that clinical response to Li treatment, measured with the Alda scale, was associated with a diminished burden of mania, depression, substance and alcohol abuse, psychosis and suicidal ideation in patients with BP-I and, in patients with BP-II, of depression only. Our genetic analyses showed that a stronger clinical response to Li was modestly related to lower polygenic load for diabetes and hypertension in BP-I but not BP-II. Moreover, our results suggested that a number of genes that have been previously linked to Li response variability in BP differentially relate to the psychiatric symptomatology, particularly to the numbers of manic and depressive episodes, and to the polygenic load for comorbid conditions, including diabetes, hypertension and hypothyroidism. Conclusions: Taken together, our findings suggest that the effects of Li on symptomatology and comorbidity in BP are partially modulated by common genetic factors, with differential effects between BP-I and BP-II. [ABSTRACT FROM AUTHOR]

Lithium has been the treatment of choice for patients with bipolar disorder. However, lithium overdose happens more frequently since it has a very narrow therapeutic range in blood, necessitating investigation of its adverse effects on blood cells. The possible changes that lithium exposure may have on functional and morphological characteristics of human red blood cells (RBCs) have been studied ex vivo using single-cell Raman spectroscopy, optical trapping, and membrane fluorescent probe. The Raman spectroscopy was performed with excitation at 532 nm light, which also results in simultaneous photoreduction of intracellular hemoglobin (Hb). The level of photoreduction of lithium-exposed RBCs was observed to decline with lithium concentration, indicating irreversible oxygenation of intracellular Hb from lithium exposure. The lithium exposure may also have an effect on RBC membrane, which was investigated via optical stretching in a laser trap and the results suggest lower membrane fluidity for the lithium-exposed RBCs. The membrane fluidity of RBCs was further studied using the Prodan generalized polarization method and the results verify the reduction of membrane fluidity upon lithium exposure. [ABSTRACT FROM AUTHOR]

Despite unlimited access to therapeutic drug monitoring lithium poisoning is still a common and potentially life-threatening but in most cases preventable complication of lithium treatment; however, it is still considered to be the gold standard in the treatment of affective disorders. The necessity of drug monitoring and potential lithium toxicity substantiate the skepticism of many therapists with respect to this often very effective treatment. This therefore limits the use of lithium although the unique therapeutic effects and high efficiency are well known. This retrospective data analysis of risk factors and etiology of lithium poisoning cases identified 58 cases of lithium poisoning, which were treated internally in this hospital between 2010 and 2014. Of the patients 67.2% were female and the majority were classified as chronic poisoning (66.1%). The most relevant patient-related risk factor seemed to be insufficient self-management as 26% of cases of lithium poisoning occurred during febrile infections or exsiccosis. Regarding practitioner-related risk factors, an insufficient consideration of drug interactions, insufficient therapeutic drug monitoring after dose increase and a paucity of experience and knowledge concerning lithium treatment were most relevant. This study illustrates the most important risk factors for lithium poisoning and their frequencies and contributes to raise awareness for this highly relevant topic. These data can help to prevent further cases of lithium poisoning. Furthermore, the results enable a comparison between the actual treatment reality and currently available evidence for the treatment of lithium poisoning. [ABSTRACT FROM AUTHOR]

Vertebrate RACK1 plays a key role in embryonic development. This paper described the cloning, phylogenetic analysis and developmental expression of AmphiRACK1, the RACK1 homologous gene in amphioxus. Phylogenetic analysis indicated that amphioxus RACK1 was located at the base of vertebrate clade. AmphiRACK1 expression in lithium-treated embryos was also examined. During embryonic development, AmphiRACK1 was expressed strongly in cerebral vesicles, neural tubes and somites. In lithium-treated embryos, the segmental expression of AmphiRACK1 in somites became blurry and decreased. Its expression in cerebral vesicles and neural tubes was also weaker or disappeared. In the adult animal, AmphiRACK1 transcripts were detected in the epithelium of midgut diverticulus and gut, wheel organ, gill blood vessels and testis. [ABSTRACT FROM AUTHOR]

In the present cross-sectional study, thyroid functions (viz. thyroid radioiodine uptake [RAIU] and serum T3, T4, and thyroidstimulating hormone [TSH]) were evaluated in 24 healthy controls and 132 outdoor affective disorder patients. Eleven of these patients were to receive lithium (Li) and the remaining 121 patients were at different stages of Li treatment ranging from 0.7 to 240 mo. RAIU was found to increase significantly throughout the Li therapy and was associated with the corresponding rise in TSH levels. In totality, Li treatment induced subclinical hypothyroidism in 51/132 (39%) of patients. However, 8/51 patients who belonged to known iodine-deficient belt had abnormally high TSH (range 15.2–76.0 uIU/mL), low T4 (5.3 ± 2.5 Hg/dL), and normal T3 and at least 4 of these 8 patients were clinically hypothyroid. T4 levels declined significantly ( p < 0.05) with Li treatment ranging from 61 to 240 mo as compared to the corresponding values in the pre-Li group. The T3/T4 ratio was found to be significantly higher with Li treatment ranging from 0.7 to 6 mo in comparison with the pre-Li group and this value returned to base levels after long-term Li therapy. High T3 and T4 were observed in 13% and 12% of the patients, respectively, as compared to the corresponding control values. [ABSTRACT FROM AUTHOR]

Rats were treated with lithium administered either via the food or by intraperitoneal injection. Lithium administration via the food results in a rather stable serum lithium concentration, whereas lithium injection results in a varying serum lithium concentration whereby a sharp increase shortly after the injection is followed by an exponential decline until the next injection (Plenge et al. 1981) After 5 months of lithium treatment the 5HT transport protein, the β-adrenergic receptor and several other brain proteins were determined. The 5HT transport protein, labelled with [H]paroxetine, was found to be decreased in the lithium-injected rats (B=347 fmol/mg protein) but was unchanged in the lithium-fed rats (B=389 fmol/mg protein), as compared with control rats (B=396 fmol/mg protein), and therefore probably is a specific effect only seen with varying lithium concentration. In contrast, the neuronal membrane marker protein D3 was decreased in the lithium-fed rats (88% of the control value), and showed a trend towards decrease in the lithium-injected rats. The decrease in D3 in the lithium-fed rats may indicate some neuronal damage due to the continous presence of lithium. This damage may be more pronounced than in rats, where periods of low lithium concentration enable repair to take place. The β-adrenergic receptor and the neural cell adhesion molecule NCAM were unaffected by the different lithium treatment regimens. Lithium has been reported to inhibit the 5HT1B receptor (the serotonin autoreceptor). We postulate that the two effects, i.e. overall lithium-induced inhibition of the 5HT autoreceptor and the down-regulation of the 5HT transport protein in rats with changing lithium concentration shown in the present study, may combine to augment the 5HT concentration in the synaptic cleft; increased 5HT in the cleft possibly being relevant in prophylactic lithium treatment of manic depressive disorders. [ABSTRACT FROM AUTHOR]

Striatal dopamine and its metabolites were studied in rats given lithium chloride in the diet. Results showed an increase in homovanillic acid and 3,4-dihydroxyphenylacetic acid levels but no significant change in dopamine concentration after 3 weeks of lithium administration. There was no change in tyrosine hydroxylase activity after 1, 2, and 3 weeks treatment. The results indicate an increase in the release and turnover of dopamine in the lithium-treated animals. [ABSTRACT FROM AUTHOR]

The impact of lead as an environmental pollutant on the I-131 uptake and retention in rat thyroid was assayed alone and in combination with lithium treatment. Lead treatment significantly stimulated the 2- and 24-h uptake of I-131 in the thyroid, and the 24-h uptake showed the maximum stimulation after 3 mo of lead treatment. On the contrary, lithium supplementation reduced the uptake significantly and the maximum decrease was noticed after 2 mo of lithium administration. Further, simultaneous lead and lithium treatment resulted in more pronounced increase in the uptake of I-131 by the thyroid, which was maximum after 3 mo of combined treatment. The thyroidal biological half-life of I-131 ( T ) was found to be increased significantly following lead and lithium treatments when given separately. Interestingly, combined lead and lithium treatment given up to 2 mo further prolonged the T of I-131, thus reflecting its increased retention. [ABSTRACT FROM AUTHOR]

Frog embryos that are treated with lithium during cleavage stages produce increased amounts of anterodorsal structures and decreased amounts of posterior and ventral structures. This alteration in pattern formation involves at least two changes in cell fate: the blastomeres that normally produce ventral structures populate anterodorsal structures, and the blastomeres that normally produce posterodorsal structures populate anterodorsal structures. The dorsalization of the ventral mesoderm has been shown to occur because Li alters the response to the ventral component of mesoderm induction. The posterior to anterior changes can be attributed to a reversal of embryonic polarity caused by a marked reduction in the dorsal involution of chordamesoderm. However, it is not known whether the reduction of chordamesodermal involution is produced secondarily by the abnormal migratory properties of the dorsalized ventral mesoderm, or whether it is caused by Li directly. In order to distinguish between these possibilities, chimeras of normal and Li-treated embryos were produced at the beginning of gastrulation. Chimeras with Li-treated ventral halves and normal dorsal halves developed into embryos with two heads and a single normal trunk, confirming the conclusion that the dorsalization of ventral mesoderm is produced directly by the Li. Chimeras with normal ventral halves and Li-treated dorsal halves developed into embryos that lacked postcephalic dorsal structures. These results indicate that the Li-produced lack of postcephalic dorsal structures does not depend on the altered ventral morphogenetic movements. The fate changes on the dorsal side of the embryo suggest that Li also alters the dorsal component of mesoderm induction. [ABSTRACT FROM AUTHOR]

Lithium chloride was administered chronically in two dose levels to rats giving serum lithium concentrations of about 0.4 and 0.7 meq/l. Treatment with the lower lithium dose did not affect monoamine metabolism in the brain. With the higher dose, accumulation of labelled 5-HT and 5-HIAA in the brain during intravenous infusion of H-tryptophan was increased. The effect was also present in the spinal cord following transection of 5-HT neurons, thus occurring independently of nerve impulse activity. The disappearance of labelled 5-HT from brain after intravenous injection of H-tryptophan was reduced in lithium-treated animals, indicating that lithium diminishes release of 5-HT from its storage sites. Brain tryptophan was augmented by lithium, whereas levels of free and total tryptophan in serum as well as its catabolism, reflected by liver tryptophan pyrrolase activity, were unaltered. Accumulation and disappearance of labelled dopamine and noradrenaline formed from C-tyrosine in brain were not changed by lithium treatment. It is concluded that chronic treatment of rats with lithium within the low dose range recommended for man affects 5-HT, but not catecholamine synthesis and turnover in brain. [ABSTRACT FROM AUTHOR]

Patients given long-term treatment with lithium often develop an impairment of renal water reabsorption which may lead to clinically significant adverse reactions. A convenient measure of this impairment may be obtained using the ratio of urine volume (V) divided by lithium clearance (C). When data from a large group of patients were recalculated, this ratio showed a statistically significant correlation with the serum lithium level. This finding supports the suggestion that patients might advantageously be maintained at lower serum levels than those commonly employed. [ABSTRACT FROM AUTHOR]