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Bipolar disorder (BD) is a psychiatric disease characterized by alternating episodes of mania and depression. Lithium (Li) represents the mainstay treatment for BD, although a significant proportion of patients shows insufficient or no response. Li is also associated with potentially severe side effects, including renal effects. Several studies reported that Li may induce reduction of glomerular filtration rate (GFR) in patients under long-term treatment. The biological systems and the genetic factors involved in susceptibility to Li-induced renal-side effects have been scarcely explored. The aim of our study was to test the contribution of putatively risk genetic variants in Li-induced reduction in estimated GFR (eGFR) in BD patients under long-term Li treatment. Tag SNPs, located in genes previously shown to be associated with kidney dysfunction or Li mechanism of action, were selected and genotyped in a sample of 70 BD patients of Sardinian origin. SNP rs378448, located in Acid Sensing Ion Channel Neurona-1 ( ACCN1 ) gene, showed a significant interaction with duration of Li treatment on eGFR (F 2 = 3.623, p = 0.033). Our preliminary findings suggest that rs378448 could predispose BD subjects to a detrimental effect of chronic Li treatment on kidney functioning. [ABSTRACT FROM AUTHOR]

Considerable research effort has been invested in attempting to understand immune dysregulation leading to autoimmunity and target organ damage. In systemic lupus erythematosus (SLE), patients can develop a systemic disease with a number of organs involved. One of the major target organs is the kidney, but patients vary in the progression of the end-organ targeting of this organ. Some patients develop glomerulonephritis only, while others develop rapidly progressive end organ failure. In murine models of SLE, renal involvement can also occur. Studies performed over the past several years have indicated that treatment with LiCl of females, but not males of the NZB/W model, at an early age during the onset of disease, can prevent development of end-stage renal disease in a significant percentage of the animals. While on Li treatment, up to 80% of the females can exhibit long-term survival with evidence of mild glomerulonephritis which does not progress to renal failure in spite of on-going autoimmunity. Stopping the treatment led to a reactivation of the disease and renal failure. Li treatment of other murine models of SLE was less effective and decreased survivorship in male BxSB mice, exhibited little effect on male MRL-lpr mice, and only modestly improved survivorship in female MRL-lpr mice. This perspective piece discusses the findings of several related studies which support the concept that protecting target organs such as the kidney, even in the face of continued immune insults and some inflammation, can lead to prolonged survival with retention of organ function. Some possible mechanisms for the effectiveness of Li treatment in this context are also discussed. However, the detailed mechanistic basis for the sex-specific effects of LiCl treatment particularly in the NZB/W model remains to be elucidated. Elucidating such details may provide important clues for development of effective treatment for patients with SLE, ~90% of which are females. [ABSTRACT FROM AUTHOR]

Abstract: Bipolar disorder (BD) is a chronic and severe psychiatric condition with an underlying component of genetic susceptibility. Mounting evidence suggests a potential role of the endogenous cannabinoid (eCB) system in the pathogenesis of BD. Here we investigated the role of genes encoding for key eCB elements on the risk of developing BD in a sample of 357BD patients and 422 healthy controls of Sardinian ancestry. Using the HapMap CEU population SNP database, we selected 25 tag Single Nucleotide Polymorphisms (tSNPs) in N-acyl phosphatidylethanolamine phospholipase D (NAPE-PLD), cannabinoid receptor 1 (CNR1) and fatty acid amide hydrolase (FAAH) genes. No significant association was reported for FAAH or CNR1. SNPs rs11487077 and rs6465903 in NAPE-PLD showed nominal association (p=0.033 and p=0.026, respectively) with BD, not significant after permutation testing. These SNPs were also tested for association with lithium response in 204 BD patients characterized for response to long-term lithium treatment, reporting no significant findings. As a whole, our results do not support a clear role of FAAH, CNR1 and NAPE-PLD in BD and lithium response. Additional studies on independent, larger samples are warranted to further explore the involvement of the eCB system in BD. [Copyright &y& Elsevier]

BackgroundPrevious cross-sectional studies report that cognitive impairment is associated with poor psychosocial functioning in euthymic bipolar patients. There is a lack of long-term studies to determine the course of cognitive impairment and its impact on functional outcome.MethodA total of 54 subjects were assessed at baseline and 6 years later; 28 had DSM-IV TR bipolar I or II disorder (recruited, at baseline, from a Lithium Clinic Program) and 26 were healthy matched controls. They were all assessed with a cognitive battery tapping into the main cognitive domains (executive function, attention, processing speed, verbal memory and visual memory) twice over a 6-year follow-up period. All patients were euthymic (Hamilton Rating Scale for Depression score lower than 8 and Young mania rating scale score lower than 6) for at least 3 months before both evaluations. At the end of follow-up, psychosocial functioning was also evaluated by means of the Functioning Assessment Short Test.ResultsRepeated-measures multivariate analysis of covariance showed that there were main effects of group in the executive domain, in the inhibition domain, in the processing speed domain, and in the verbal memory domain (p<0.04). Among the clinical factors, only longer illness duration was significantly related to slow processing (p=0.01), whereas strong relationships were observed between impoverished cognition along time and poorer psychosocial functioning (p<0.05).ConclusionsExecutive functioning, inhibition, processing speed and verbal memory were impaired in euthymic bipolar out-patients. Although cognitive deficits remained stable on average throughout the follow-up, they had enduring negative effects on psychosocial adaptation of patients. [ABSTRACT FROM AUTHOR]

Background: The adverse renal effects of lithium have long been known, but glomerular insufficiency had been considered an unlikely event until recently, when new studies have raised concern regarding very long-term treatment. In this cross-sectional study, we examined glomerular function in a cohort of patients treated with lithium for up to 33 years and a control group of lithium-naïve patients treated with other mood-stabilizers. Methods: Patients with a diagnosis of recurrent or persistent affective disorders, examined between 1 October 2007 and 31 December 2009, were screened. Demographic and clinical data were extracted from clinical charts regarding two study groups: one for patients treated with lithium for at least 12 months and the other for patients never exposed to lithium. Multivariate regression analysis was applied: the dependent variable was the estimated glomerular filtration rate (eGFR) calculated from the last available serum creatinine value using the Modification of Diet in Renal Disease Study Group equation; the following independent variables, potentially associated with renal dysfunction, were included: gender, current age, duration of lithium treatment, cigarette smoking, hypertension, diabetes and dyslipidemia. Results: eGFRs lower than 60 ml/min were significantly more frequent in the group treated with lithium (38/139 = 27.3%) compared to lithium-naïve patients (4/70 = 5.7%) (P = 0.0002; Fisher's test). Regression analysis showed a significant effect on eGFR of age, gender and duration of lithium treatment but no effect of cigarette smoking, hypertension, diabetes or dyslipidemia. eGFR was estimated to decrease by 0.64 ml/min (95% confidence interval = 0.38 to 0.90; P = 0.00) for each year of lithium treatment. Conclusions: The duration of lithium treatment is a risk factor for glomerular failure, in addition to advancing age. For example, all patients aged 60 years or older may be estimated to undergo Stage 3 or more severe chronic kidney disease (namely an eGFR less than 60 ml/min) if treated with lithium for 30 years. These data may be added to the current debate on the balance between the protective effects of lithium on recurrent affective disorders and suicide and the risk of renal disease [ABSTRACT FROM AUTHOR]

ABSTRACT Severe dental decay and changes in tooth structure have been reported in association with the use of lithium in Psychiatry, but lithium effects on tooth inorganic composition remain unknown. A 30-year-old woman with bipolar disorder, treated with lithium carbonate presented severe dental decay. Dentin samples from lithium and healthy volunteers were collected and submitted to ionic and ultrastructural analysis. Samples from the lithium patient exhibited irregular peritubular walls and the mineral crystals were irregularly arranged in the intertubular dentin. In addition, a decrease in Mg/P/Ca and an increase of Zn concentrations were detected. These data suggest that the severe dental decay and changes in the tooth structure observed for the lithium-treated patient are related to dentin mineral loss and that this pathological condition is different from caries lesions. [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]

Abstract: Background: Non-adherence should always be investigated when there is a failure in bipolar treatments, since it is known that reported non-adherence rates in bipolar disorder treatment for long-term prophylactic pharmacotherapy range from 18% to 52%, with a median prevalence of 44.7%. Several factors are related to the poor adherence and reduction of medication efficiency, such as the different types of bipolar disorder, the presence of side effects, medication interactions, level of patient''s knowledge about the disorder and their attitude towards treatment, complexity of medical regimens and the doctor–patient relationship. Methods: Bipolar disorder outpatients under lithium treatment from the Hospital de Clínicas and Materno Infantil Presidente Vargas of Porto Alegre were recruited. All the patients had bipolar disorder and gave informed consent to participate in a clinical interview (106), answered the Lithium Attitudes Questionnaire (LAQ), Lithium Knowledge Test (LKT), Medication Adherence Rating Scale (MARS) and had plasma and red blood cells lithium measurements to assess their medication adherence and the factors that influenced it. Results: 85.6% of bipolar disorder were adherent to lithium treatment showing plasma lithium between 0.6 and 1.2 mmol/L. There was an inverted correlation between the total LAQ score with plasma and red blood cells, a positive correlation between LKT and MARS with plasma and red blood cell lithium. Conclusion: These results confirmed that knowledge level is directly correlated to treatment adherence and patients'' attitudes, lower adherence, general opposition to prophylaxis, fear of side effects, denial of therapeutic effectiveness and illness severity. [Copyright &y& Elsevier]

Introduction: Lithium is a well-known drug and frequently a key factor in the management of acute mania, unipolar and bipolar depression and prophylaxis of bipolar disorders. However, its effect on thyroid function cannot be overlooked, with numerous reports of thyroid abnormalities' onset during tretament with lithium. Objectives: To assess the prevalence, risk factors and management of thyroid disfunction in patients undergoing lithium therapy. Methods: Non-systematic review of the literature from Pubmed database, using the key words: lithium treatment, lithium toxicity, thyroid dysfunction, goitre, hypothyroidism, hyperthyroidism, thyroid autoimmunity. Results: Our assessment has identified female sex, middle age, autoimmune disease or the history of thyroid disease in the family as risk factors for the development of thyroid abnormalities while undergoing lithium therapy (the most common being goiter and hypothyroidism). It is recommended that thyroid function tests and assessment of thyroid size are performed among patients initiating lithium therapy, at baseline and later annually (more frequently among patients presenting risk factors). Conclusions: We find it important to stress that the development of thyroid dysfunction does not typically require discontinuation of lithium. Lithium should not be stopped unless its serum concentration is beyond the therapeutic range. Instead, supplementation with levothyroxine should be started (according to specific indications). Clinicians managing lithium-treated patients must keep thyroid disorders in mind, and screen them clinically and through thyroid function tests during follow-up in order to institute early and appropriate treatment. [ABSTRACT FROM AUTHOR]

Abstract: Glutamate is the most abundant excitatory neurotransmitter in the mammalian brain, and it is increasingly being implicated in the pathophysiology of mental illness. In fact, changes in glutamate neurotransmission seem to be involved in the etiology of schizophrenia, major depression and bipolar disorders. Furthermore, the alterations in platelet sensitivity in major depression are distinct from those of bipolar disorders. The aim of the present investigation was to determine whether patients with bipolar disorders exhibited differences in [3H]-glutamate uptake of platelets. [3H]-Glutamate uptake of platelets from controls (n =14), patients with bipolar disorders under lithium treatment (600–1800 mg/day for 6 months) (n =7) and patients with bipolar disorders with psychotic features (n =8) were carried out. Analysis of blood platelets from the three groups of subjects revealed significant differences in [3H]-glutamate uptake between the control and psychotic patients. The specific glutamate uptake for the control and psychotic groups was 20.5±8.4 and 37.5±18.1 pmol glutamate/mg protein/10 min, respectively (mean±SD). These results indicate that peripheral glutamate metabolism of platelets is modified in bipolar disorders and that more detailed studies must be carried out to determine whether these peripheral modifications correlate with central modifications in humans and in animal models of the disease. [Copyright &y& Elsevier]

Background: Our knowledge concerning immune functioning in bipolar affective disorder (BAD) is limited, while lithium''s immunomodulatory effects seem multiple and conflicting. Our aim was to evaluate cytokine production and lithium''s effect on it in BAD patients, using ELISPOT technique as a sensitive tool. Methods: Cytokine (IL-2, IL-6, IL-10 and IFN-γ) production from isolated peripheral blood lymphocytes (PBLs) was evaluated (ELISPOT technique) in 40 euthymic BAD patients under chronic lithium treatment, in 20 healthy volunteers, and in 10 never medicated BAD patients before and after the introduction of lithium therapy. In all cases, cytokine plasma levels were also measured using ELISA. Results: BAD patients under chronic lithium treatment had significantly lower numbers of IL-2, IL-6, IL-10 and IFN-γ secreting cells compared to healthy volunteers. The number of cytokine secreting cells decreased in never medicated patients after 3 months of lithium treatment. In vitro stimulation of PBLs with lithium did not affect the number of cytokine secreting cells either in the patients or in the healthy volunteers. Conclusions: The significantly lower number of PBLs producing cytokines (IL-2, IL-6, IL-10 and IFN-γ) in euthymic BAD patients under chronic lithium treatment result from the long-term (over 3 months) lithium administration. In vitro stimulation of PBLs with lithium did not change the number of cytokine producing cells. Our findings may be useful in elucidating possible downregulatory effects of lithium in humans. [Copyright &y& Elsevier]

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]

Background. Controversy remains over the magnitude and reversibility of reduced renal function in long-term lithium patients. Method. Thirteen patients with 18 years (range 15–24) on lithium discontinued the treatment, and were re-examined twice after 5 and 9 weeks (4–16) off lithium. They were compared to a non-lithium psychiatric control group, matched for age and sex. Results. Glomerular filtration rate (GFR) tended to improve from 69 (39–96) to 74 (39–94) ml/min/1.73 m2 BSA, P=0.057, which was not significantly different from 78 (61–106 ml/min per 1.73 m2 BSA in the controls. Reduced GFR was found in only two of the lithium patients off lithium, and in none of the controls. Maximal urinary concentrating capacity did not improve at all. It was 637 (130–875) mOsm/kg H2O in the lithium patients, which was lower than 856 (705–1.035) mOsm/kg H2O (P<0.01) in the controls. Two of the lithium patients had isosthenuria. Conclusions. Lithium patients often have an irreversible, clinically important reduction of Umax, sometimes progressing to nephrogenic diabetes insipidus, while GFR is well preserved in most patients. [ABSTRACT FROM PUBLISHER]

The renal risks associated with long-term lithium treatment are a growing concern. We have therefore studied renal function by means of glomerular filtration rate (GFR) and maximum urinary concentrating capacity (Umax) in 142 of 215 patients with more than 15 years of lithium treatment in nine psychiatric clinics. Data on psychiatric and somatic diseases, hospital admissions, cumulative lithium doses, and other psychotropic treatments were extracted from the medical records. The patients were investigated according to a standardized protocol. GFR was measured as Cr EDTA clearance and Umax using the DDAVP test. Thirteen patients had had signs of lithium intoxication. GFR was reduced in 21% of the patients and Umax in 44%. Nephrogenic diabetes insipidus was present in 12%. Umax but not GFR was inversely correlated to the cumulative lithium dose. Kidney function was more reduced in patients on lithium combined with psychotropic treatment and/or concomitant treatment for somatic disorders. Thirst was a complaint of 53% of the patients, predominantly those with additional psychotropics. We conclude that kidney damage is common in patients on long-term lithium treatment and that both glomerular and tubular function are affected. [ABSTRACT FROM PUBLISHER]

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]

Mood disorders are chronic, recurrent diseases characterized by changes in mood and emotions. The most common are major depressive disorder (MDD) and bipolar disorder (BD). Molecular biology studies have indicated an involvement of the immune system in the pathogenesis of mood disorders, and showed their correlation with altered levels of inflammatory markers and energy metabolism. Previous reports, including meta-analyses, also suggested the role of microglia activation in the M1 polarized macrophages, reflecting the pro-inflammatory phenotype. Lithium is an effective mood stabilizer used to treat both manic and depressive episodes in bipolar disorder, and as an augmentation of the antidepressant treatment of depression with a multidimensional mode of action. This review aims to summarize the molecular studies regarding inflammation, microglia activation and energy metabolism changes in mood disorders. We also aimed to outline the impact of lithium on these changes and discuss its immunomodulatory effect in mood disorders. [ABSTRACT FROM AUTHOR]