Effect Of Long-term Lithium Treatment Research Articles

Telomere length attrition correlated with age in male bipolar patients with no effect of long-term lithium-treatment

Telomere length attrition correlated with age in male bipolar patients with no effect of long-term lithium-treatment

Decreased leucocyte telomere length in male patients with chronic bipolar disorder: lack of effect of long-term lithium treatment.

Bipolar disorder (BD) may be connected with accelerated aging, the marker of this can be shorter telomere length (TL). Some data suggest that lithium may exert a protective effect against telomere shortening. The study aimed to compare the TL between patients with BD and control subjects. The effect of long-term lithium treatment was also assessed. The study group comprised 41 patients with BD, including 29 patients treated longitudinally with lithium (mean 16.5 years) and 20 healthy people. TL was assessed by the quantitative polymerase chain reaction (qPCR). In the control group, the TL was significantly longer in males than in females. Male bipolar patients had significantly shorter TL compared with the control male group. In bipolar patients, there was no correlation between TL and duration of treatment. The TL was negatively correlated with age in male bipolar patients. The study did not confirm the lithium effect on TL in bipolar patients. TL showed gender differences, being shorter in BD males, compared to control males, and longer in healthy males, compared to control females.

The association between anti-inflammatory effects of long-term lithium treatment and illness course in Bipolar Disorder.

Introduction: Altered levels of acute-phase proteins are often described in different conditions in BD. Nevertheless, data on the association between lithium treatment and inflammatory markers in the long-term course of BD are still missing. The aim of the study was to examine the long-term course of BD concerning long-term lithium treatment, chronic inflammatory processes and symptom progression. Furthermore, the association between duration of lithium treatment and levels of hsCRP was explored. Methods: 267 individuals (males= 139, females= 128) with BD were included. Duration of lithium treatment as well as symptom progression, defined as the increase in severity of symptoms, number of episodes a year and duration of episodes within a period of 1.5 years in the past and hsCRP were evaluated. Results: Male individuals with symptom progression over time had significantly lower duration of lithium treatment compared to individuals without symptoms progression (U= 47.4, p=.037). There were significantly higher levels of hsCRP in male individuals with symptom progression compared to males without symptom progression (U= 47.5, p=.027). Further, there was a significant negative correlation between the duration of lithium treatment and hsCRP levels in the whole sample (r= -.276, p<.05). Conclusion: Our results show that an altered inflammatory state may be associated with a more severe illness course in BD. Further, a longer duration of lithium treatment may be associated with lower symptom progression. The shown association between hsCRP-levels and lithium treatment duration suggests a potential anti-inflammatory effect of lithium as a mediator of its significant positive outcome effect in BD.

Effects of Long-Term Endurance Exercise and Lithium Treatment on Neuroprotective Factors in Hippocampus of Obese Rats.

To investigate the effects of long-term lithium treatment and low intensity endurance exercise on brain-derived neurotrophic factor (BDNF) expression and glycogen synthase kinase 3 beta (GSK3β) activity in the hippocampus of obese rats. Fifty 10-week-old male Sprague-Dawley rats were selected. There was a control group of 10 rats (chow control group) while the other forty rats were fed on a high-fat diet for eight weeks to induce obesity. Rats were then assigned into four random groups. The rats were given 10 mg/kg lithium chloride (LiCl) dissolved in 1 mL sterile distilled water once a day, 5 times a week. The rats did 20 min of treadmill walking with an exercise intensity of 40% maximal oxygen uptake (VO2 max) (12 m/min, slope 0%). This was performed for 20 min a day, 3 days a week. Twelve weeks of lithium treatment or endurance exercise significantly reduced body weight and body fat mass in obese rats, without showing additive effects when the treatments were given in parallel or significant toxic responses in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels in blood and kidney and liver tissues. BDNF expression in the hippocampus was significantly increased both in exercise and lithium groups with synergistic effects found in the group where both exercise and lithium treatments were given in parallel. On the other hand, the decrease in GSK3β activity was shown only in the lithium treatment group, without showing additive effects when the treatments were given in parallel. Lithium and low-intensity endurance exercise for 12 weeks increased the expression of BDNF, a neuroprotective factor in the hippocampus of obese mice. Lithium treatment alone inhibited the activity of GSK3β. This can be interpreted as a positive indication of applicability of the two factors in the prevention of neurodegenerative diseases.

Clinical and biological effects of long-term lithium treatment in older adults with amnestic mild cognitive impairment: randomised clinical trial.

Experimental studies indicate that lithium may facilitate neurotrophic/protective responses in the brain. Epidemiological and imaging studies in bipolar disorder, in addition to a few trials in Alzheimer's disease support the clinical translation of these findings. Nonetheless, there is limited controlled data about potential use of lithium to treat or prevent dementia. To determine the benefits of lithium treatment in patients with amnestic mild cognitive impairment (MCI), a clinical condition associated with high risk for Alzheimer's disease. A total of 61 community-dwelling, physically healthy, older adults with MCI were randomised to receive lithium or placebo (1:1) for 2 years (double-blind phase), and followed-up for an additional 24 months (single-blinded phase) (trial registration at clinicaltrials.gov: NCT01055392). Lithium carbonate was prescribed to yield subtherapeutic concentrations (0.25-0.5 mEq/L). Primary outcome variables were the cognitive (Alzheimer's Disease Assessment Scale - cognitive subscale) and functional (Clinical Dementia Rating - Sum of Boxes) parameters obtained at baseline and after 12 and 24 months. Secondary outcomes were neuropsychological test scores; cerebrospinal fluid (CSF) concentrations of Alzheimer's disease-related biomarkers determined at 0, 12 and 36 months; conversion rate from MCI to dementia (0-48 months). Participants in the placebo group displayed cognitive and functional decline, whereas lithium-treated patients remained stable over 2 years. Lithium treatment was associated with better performance on memory and attention tests after 24 months, and with a significant increase in CSF amyloid-beta peptide (Aβ1-42) after 36 months. Long-term lithium attenuates cognitive and functional decline in amnestic MCI, and modifies Alzheimer's disease-related CSF biomarkers. The present data reinforces the disease-modifying properties of lithium in the MCI-Alzheimer's disease continuum. None.

The effect of long-term lithium treatment on renal functions in patients with bipolar disorder

IntroductionThe effect of lithium on tubular functions leading to decreased urinary concentrating ability is recognized. Although there are several studies type, severity and frequency of renal impairment and its correlation with duration of lithium therapy are not well established.ObjectivesTo explore long-term effects of lithium on patients with chronic bipolar disorder.AimsWe aimed to assess patients with bipolar disorder using lithium at least for six years in terms of renal functions, starting from mild impairments to full blown chronic renal failure.MethodsFifty-one patients with bipolar disorder and 38 age and sex matched healthy controls were enrolled for the study. Serum BUN, creatinine, uric acid, electrolytes, calcium (Ca), phosphorus (P), vitamin D (25-OH D3) and eGFR levels were measured. The correlations between renal function and mean lithium levels, duration of lithium treatment and GAF scores were calculated.ResultsMean eGFR level of patients with bipolar disorder was significantly lower than that of controls. Serum creatinine, uric acid, Ca and PTH levels were higher, 25-OH D3 levels were lower in the patients than in controls. The duration of lithium treatment was positively correlated with serum creatinine and uric acid levels, negatively correlated with eGFR levels. Mean lithium levels were positively correlated with serum creatinine levels and negatively correlated with eGFR.ConclusionsThe study revealed that glomerular functioning of the patient group was significantly lower than that of the control group. The findings suggested that both duration of lithium treatment and high serum lithium levels may have a negative impact on glomerular functions.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Increased mRNA expression of peripheral glial cell markers in bipolar disorder: The effect of long-term lithium treatment

Neuroinflammation, with microglial activation as an important element, plays a role in the pathogenesis of bipolar disorder (BD). Also, in mood disorders, pathological changes have been demonstrated in macroglial cells, such as astrocyctes and oligodendrocytes. Postmortem brain studies of BD patients to assess glial cells, such as astrocytes and oligodendrocytes and their markers such as glial fibrillary acidic protein (GFAP), Olig1 and Olig2, produced controversial results. On the other hand, investigation of these markers in the peripheral blood of such patients has not been performed so far. In this study, we examined the mRNA levels of GFAP, Olig1 and Olig2, in the peripheral blood of three groups: 15 BD subjects with a duration of illness at least 10 years (mean 20±9 years) but never treated with lithium, 15 subjects with BD treated continuously with lithium for 8–40 years (mean 16±8 years), and 15 control subjects. The groups were age-and sex-matched. Expression of mRNA markers was measured by real-time quantitative reverse transcription PCR (RQ-PCR). We observed increased mRNA levels of the Olig1 and Olig 2 glial markers studied in the BD patients not taking lithium, compared with the control subjects and increased mRNA level of GFAP, compared with lithium-treated patients. In the lithium-treated BD patients GFAP and Olig1 expression was at similar levels to that in the control group. However, Olig 2 expression was even higher than in the BD patients not taking lithium. The possible mechanisms concerning the higher expression of peripheral mRNA markers in BD patients may involve ongoing inflammatory process, compensatory mechanisms and regenerative responses. The beneficial effect of lithium may be related to its anti-inflammatory properties.

Peripheral mRNA expression of pluripotency markers in bipolar disorder and the effect of long-term lithium treatment.

The aim was to evaluate the peripheral mRNA expression of pluripotency master transcriptional factors such as octamer-binding transcription factor 4 (Oct4), sex-determining region Y-box 2 (Sox2) and homeobox protein Nanog, in patients with bipolar disorder (BD), and the effect of long-term lithium treatment. Fifteen BD patients (aged 53±7years) not treated with lithium, with duration of illness>10years, 15 BD patients (aged 55±6years) treated with lithium for 8-40 years (mean 16years) and 15 control subjects (aged 50±5years) were included. Assessment of the mRNA levels of pluripotency markers (Oct-4, Sox 2 and Nanog) was performed, using the Real-time quantitative reverse transcription PCR (RQ-PCR) procedure, and the number of CD34+ very small embryonic-like stem cells (VSELs) was measured by flow cytometric analysis. In those BD patients not treated with lithium the expression of all three pluripotency genes was significantly higher than that in the control subjects. Oct-4, Sox2 and Nanog also positively correlated with the number of CD34+ VSELs/[ul] in this group. In the lithium-treated patients the mRNA levels of Nanog were significantly higher than in the control individuals and correlated with the number and % of CD34+ VSELs. The overexpression of the pluripotency master transcriptional factors in patients with a long duration of BD not treated with lithium, may contribute to the pathogenesis of the illness and make them potential biological markers of BD. Long-term lithium treatment may attenuate these excessive regenerative processes, especially in relation to the transcription factors Oct-4 and Sox2.

The effect of long-term lithium treatment of bipolar disorder on stem cells circulating in peripheral blood

Objectives: To investigate the effect of long-term lithium treatment on very small embryonic-like stem cells (VSELs), haematopoietic stem cells (HSCs), mesenchymal stem cells (MSCs) and endothelial progenitor cells (EPCs) circulating in peripheral blood (PB), in bipolar disorder (BD).Methods: The study included 15 BD patients (aged 55 ± 6 years) treated with lithium for 8–40 years (mean 16 years), 15 BD patients (aged 53 ± 7 years) with duration of illness >10 years, who had never received lithium, and 15 healthy controls (aged 50 ± 5 years). The VSELs, HSCs, MSCs and EPCs were measured by flow cytometric analysis.Results: In BD subjects not taking lithium the number of CD34+ VSELs was significantly higher, and MSCs and EPCs numerically higher, than in control subjects and the number of CD34+ VSELs correlated with the duration of illness. In lithium-treated patients these values were similar to controls and the number of CD34+ VSELs correlated negatively with the duration of lithium treatment and serum lithium concentration.Conclusions: Long-term treatment with lithium may suppress the activation of regenerative processes by reducing the number of VSELs circulating in PB. These cells, in BD patients not treated with lithium, may provide a new potential biological marker of the illness and its clinical progress.

Inositol-Deficient Food Augments a Behavioral Effect of Long-Term Lithium Treatment Mediated by Inositol Monophosphatase Inhibition

Lithium treatment in rodents markedly enhances cholinergic agonists such as pilocarpine. This effect can be reversed in a stereospecific manner by administration of inositol, suggesting that the effect of lithium is caused by inositol monophosphatase inhibition and consequent inositol depletion. If so, inositol-deficient food would be expected to enhance lithium effects. Inositol-deficient food was prepared from inositol-free ingredients. Mice with a homozygote knockout of the inositol monophosphatase 1 gene unable to synthesize inositol endogenously and mimicking lithium-treated animals were fed this diet or a control diet. Lithium-treated wild-type animals were also treated with the inositol-deficient diet or control diet. Pilocarpine was administered after 1 week of treatment, and behavior including seizures was assessed using rating scale. Inositol-deficient food-treated animals, both lithium treated and with inositol monophosphatase 1 knockout, had significantly elevated cholinergic behavior rating and significantly increased or earlier seizures compared with the controls. The effect of inositol-deficient food supports the role of inositol depletion in the effects of lithium on pilocarpine-induced behavior. However, the relevance of this behavior to other more mood-related effects of lithium is not clear.

Long-term, low-dose lithium treatment does not impair renal function in the elderly: a 2-year randomized, placebo-controlled trial followed by single-blind extension.

Recent studies evaluated the disease-modifying properties of lithium in mild cognitive impairment and dementia. Although potentially effective for these purposes, chronic lithium use in regard to safety in the elderly needs to be better explored. To evaluate the effect of long-term lithium treatment at subtherapeutic doses on renal function in older adults. Secondary aims were to evaluate the clinical safety and tolerability of this treatment and its effects on thyroid, immune, and glycemic functions. Between February 2007 and October 2011, a 2-year randomized, double-blind, placebo-controlled trial followed by a single-blinded phase for an additional 2 years. Sixty-one patients with mild cognitive impairment (Mayo Clinic criteria) were randomized to receive lithium or placebo. Renal function was estimated by the abbreviated Modification of Diet in Renal Disease (aMDRD) and the Chronic Kidney Disease-Epidemiology study (CKD-EPI) equations. Leukocytes, serum thyroid-stimulating hormone (TSH) and free thyroxine (T₄), and serum glucose and insulin were determined. Tolerability was evaluated at 3-month intervals through systematic clinical examinations and by the UKU Side Effect Rating Scale. Analysis of longitudinal regression indicated that no significant changes in renal function were detected by the aMDRD (P = .453) and CKD-EPI (P = .213) equations after 4 years of lithium treatment. Significant increases in the number of neutrophils (P = .038), serum TSH (P = .034), and body weight (P = .015) were observed in the lithium group. The lithium group presented more overall adverse events (P = .045), particularly interfering in daily activities (P < .001). In addition, those patients had a higher incidence of diabetes mellitus (P = .037) and arrhythmia (P = .028). Chronic use of lithium at low doses did not affect renal function and was clinically safe. However, some other potentially relevant adverse events were observed and others could not be ruled out due to limitations of the study design. ClinicalTrials.gov identifier: NCT01055392.

Lithium Is Associated with Hypercalcemia and Hyperparathyroidism

Hypothyroidism and impaired renal function are well-known adverse effects of long-term lithium treatment. Lithium has also been associated with

Long-term lithium treatment in bipolar disorder is associated with longer leukocyte telomeres

Telomere shortening is a hallmark of aging and has been associated with oxidative stress, inflammation and chronic somatic, as well as psychiatric disorders, including schizophrenia and depression. Additionally, antidepressants have been found to protect against telomere shortening. However, pharmacological telomere studies are lacking in bipolar disorder (BD). Therefore, the objective of this study was to explore telomere length (TL) in patients with BD in the context of lithium treatment. We determined TL by quantitative real-time PCR using peripheral blood leukocytes. Participants were outpatients diagnosed with BD type 1 or 2 (n=256) and healthy controls (n=139). Retrospective case–control and case–case study designs were applied. Lithium response (LiR) was scored using the Alda-Scale. Lithium-treated BD patients overall, as well as those on lithium monotherapy, had 35% longer telomeres compared with controls (P<0.0005, partial η2=0.13). TL correlated positively with lithium treatment duration of >30 months (P=0.031, R2=0.13) and was negatively associated with increasing number of depressive episodes (P<0.007). BD patients responding well to lithium treatment had longer telomeres than those not responding well. This is the first study to report a positive effect of long-term lithium treatment on TL. Importantly, longer TL was also associated with a better LiR in BD patients. These data suggest that lithium exerts a protective effect against telomere shortening especially when therapeutically efficacious. We hypothesize that induction of telomerase activity may be involved in LiR in BD.

Disease-modifying properties of long-term lithium treatment for amnestic mild cognitive impairment: randomised controlled trial

Two recent clinical studies support the feasibility of trials to evaluate the disease-modifying properties of lithium in Alzheimer's disease, although no benefits were obtained from short-term treatment. To evaluate the effect of long-term lithium treatment on cognitive and biological outcomes in people with amnestic mild cognitive impairment (aMCI). Forty-five participants with aMCI were randomised to receive lithium (0.25-0.5 mmol/l) (n = 24) or placebo (n = 21) in a 12-month, double-blind trial. Primary outcome measures were the modification of cognitive and functional test scores, and concentrations of cerebrospinal fluid (CSF) biomarkers (amyloid-beta peptide (Aβ(42)), total tau (T-tau), phosphorylated-tau) (P-tau). NCT01055392. Lithium treatment was associated with a significant decrease in CSF concentrations of P-tau (P = 0.03) and better perform-ance on the cognitive subscale of the Alzheimer's Disease Assessment Scale and in attention tasks. Overall tolerability of lithium was good and the adherence rate was 91%. The present data support the notion that lithium has disease-modifying properties with potential clinical implications in the prevention of Alzheimer's disease.

Implications of the neuroprotective effects of lithium for the treatment of bipolar and neurodegenerative disorders.

Bipolar disorder is increasingly recognized as an illness that may progress to impairment in neurocognitive functioning and cell loss in cortical and limbic brain regions. Glutamatergic damage and/or damage due to high glucocorticoid levels that inhibit adult neurogenesis are likely contributing mechanisms. Drug treatments with possible neuroprotective effects are becoming increasingly important both clinically and as research tools. Mood stabilizing drugs and lithium in particular may act to prevent neuronal damage and tissue loss that may occur in the brain of patients with bipolar disorders. Lithium has been shown to exert neuroprotective effects in vitro and to stimulate neurogenesis in the hippocampus. Animal studies have demonstrated pharmacological effects of lithium suggestive of its role in neuroprotection, which range from reducing excitotoxicity through increased glutamate uptake, to regulation of a number of signal transduction intermediates such as myo-inositol, protein kinase C, phosphotidylinositol-3 kinase (PI-3K)/protein kinase B (Akt), ras-mitogen-activated protein kinase (MAPK), glycogen synthase kinase (GSK)-3alpha and -3beta and calcium. It remains to be established whether lithium treatment protects against possible cell damage in the same manner as it protects against recurrences of the illness. We propose to examine the effect of long-term lithium treatment on neurocognitive functioning of bipolar patients and the use of lithium in the treatment of chronic neuropsychiatric disorders.

Effects of long-term lithium treatment on monoaminergic functions in major depression

Platelet [ 14C]serotonin uptake, the density of serotonin transporters and 5HT 2 receptors, and 5HT 2 and alpha 2 receptor function in platelets were investigated in 29 outpatients (15 women and 14 men) diagnosed as having a major affective disorder (21 bipolar and 8 unipolar). The data were compared with data for 26 healthy volunteers matched for age, sex and season. No differences were found in the mean values for the uptake velocity ( V max) and the affinity ( K m) of the transport carrier for serotonin between patients and controls. However, female patients had lower V max compared to male patients and female control subjects. A positive correlation between plasma lithium and V max and a tendency toward a negative correlation between plasma lithium and K m was observed. Furthermore, there were no differences in platelet B max and K d for [ 3H]paroxetine binding and K d for [ 3H]LSD binding between patients and controls. However, there was an increased number of platelet 5-HT 2 receptors and a difference in serotonin-mediated potentiation of platelet ATP secretion between patients compared to controls, especially in women. The findings in the present study suggest that lithium has a net ameliorating impact on serotonin uptake which may render it resistant to change. They also postulate that the effect of lithium may be attained by a dual influence on postsynaptic serotonergic structures, as it increases both the density and the sensitivity of 5-HT 2 receptors.

Effects of long-term lithium treatment on monoaminergic and neuroendocrine functions in major depression

Effects of long-term lithium treatment on monoaminergic and neuroendocrine functions in major depression

Effect of chronic lithium chloride on membrane adenosine triphosphatases in certain postural muscles of rats

Lithium has been extensively used as an antidepressant in the treatment of manic depressive disorders requiring chronic administration. Here, we report a study of the effect of long-term lithium treatment on the activities of membrane adenosine triphosphatases (ATPases) in certain postural muscles of rat. Specifically, Ca 2+-ATPase, Na +,K +-ATPase and Mg 2+-ATPase activities were measured in the soleus, extensor digitorum longus and plantaris muscles following 6 weeks of treatment with LiCl. Increases were observed in the Na +,K +-ATPase activity whereas the Mg 2+-ATPase activity decreased with prolonged LiCl treatment. The most pronounced effect was a highly significant ( P<0.001) increase in the mitochondrial Ca 2+-ATPase and Na +,K +-ATPase activity to almost 50–100% above the control. The increases in the mitochondrial Ca 2+-ATPase activity of extensor digitorum longus and plantaris were 70% and 100%, respectively. The corresponding increases in the Na +,K +-ATPase activity were 127%, 99% and 87% for soleus, extensor digitorum longus and plantaris, respectively. Irrespective of the differences in the fiber pattern and physiological function, all three muscles responded in a similar way to Li +. The changes in the membrane ATPases reflect a deranged ATP turnover, thus affecting the overall energy state of the animal. Based on these results, we hypothesize that Li + produces its effects by interfering with cation transport processes. Since Li + affects the neural excitability of the cell it is suggested that the stimulation of the ATPases may be important in the psychotropic properties of the ion.

Effect of Long-Term Lithium Treatment on High K+ -Induced NA, DA and 5-HT Releases in the Rat Medial Prefrontal Cortex: An In Vivo Microdialysis Study

Effect of Long-Term Lithium Treatment on High K+ -Induced NA, DA and 5-HT Releases in the Rat Medial Prefrontal Cortex: An In Vivo Microdialysis Study

Long-term lithium treatment selectively reduces receptor-coupled inositol phospholipid hydrolysis in rat brain

Rats were treated with dietary lithium for 30 days, followed by assessment of the activity of the receptor-coupled inositol phospholipid second messenger-producing system in three brain regions. The major effect of long-term lithium treatment was a significant reduction of the response to norepinephrine in all three brain regions that were examined: the cerebral cortex, the hippocampus, and the striatum. After long-term lithium treatment, the response to serotonin was reduced in the hippocampus and striatum, but not the cortex, and the carbachol-induced response was only reduced in the striatum. Lithium treatment did not alter the incorporation of [3H] inositol into phospholipids, the in vitro lithium concentration-dependent accumulation of [3H]inositol monophosphate, or the stimulation by NaF of inositol phospholipid hydrolysis. These results indicate that the decreased responses to agonists after long-term lithium treatment are not likely to be due to depletion of inositol phospholipids or to altered activity of myo-inositol-1-phosphatase, phospholipase C, or the guanine nucleotide-binding protein. It is suggested that long-term lithium treatment may alter receptor number or receptor coupling, perhaps by phosphorylotion, thereby selectively lowering the agonist-induced generation of second messengers by the inositol phospholipid system.