Long-term Administration Of Lithium Research Articles

Impact of Lithium on the Immune System: An Investigation of T-Cell Subpopulations and Cytokine Responses in Rats.

The aim of this study was to investigate the dose-dependent adverse effects of long-term dietary lithium administration on specific aspects of the defense system in rats. Additionally, the study aimed to explore the inflammatory activities of lithium beyond its recognized anti-inflammatory properties. Forty Wistar Albino rats were involved, which were randomly allocated into the control and four treatment groups. The control group received standard rat feed, and the experimental groups' diet was added 1g/kg, 1.4g/kg, 1.8g/kg, and 2.2g/kg lithium bicarbonate, respectively. CD4+, CD8+, and CD161 + cells were assessed by flow cytometry. TNF-α, IFN-γ, IL-1β, and IL-2 and IL-4, IL-6, and IL-10 levels were measured. The proportion of CD4 + cells and the CD4+/CD8 + ratio (P = 0.005 and P = 0.038, respectively) were reduced with the highest dose of lithium compared to the control group. The data regarding pro-inflammatory cytokines showed a dose-dependent increase in serum TNF-α and IFN-γ levels (P = 0.023 and P = 0.001, respectively). On the other hand, serum IL-1β and IL-2 levels were decreased in a dose-dependent manner (P = 0. 001 and P = 0. 001, respectively). As for anti-inflammatory cytokines, a dose-dependent decrease was determined in serum IL-4 level (P = 0.002), while no significant changes were noted in IL-6 and IL-10 levels (P = 0.507 and P = 0.732, respectively). In conclusion, lithium adversely impacted the cellular defense system. Furthermore, apart from its anti-inflammatory properties, lithium exhibited cytokine-mediated inflammatory activities. Therefore, lithium's potential adverse effects on the immune system should be considered in immunodeficient patients and those with an inflammatory status treated with high doses of lithium.

The effect of chronic lithium treatment on hippocampal progenitor cells: Transcriptomic analysis and systems pharmacology.

To identify the genomics underpinning the increased volume of the hippocampus after long-term administration of lithium (Li) in bipolar disorder patients, hypothesizing the possible contribution of cell growth and differentiation pathways to this complication. RNA-seq profiles of four samples of hippocampal progenitor cells chronically treated with a high dose of Li and three samples chronically treated with the therapeutic dose were retrieved from NCBI-GEO. The raw data underwent filtration, quality control, expression fold change, adjusted significance, functional enrichment, and pharmacogenomic analyses. CCND1, LOXL2, and PRNP were identified as the genes involved in the drug response and the chronic effects of Li in the hippocampal cells. GSK-3β was also a hub in the pharmacogenomic network of Li. In addition, ZMPSTE24 and DHX35 were identified as the important genes in lithium therapy. As shown by gene ontology results, these findings conclude that lithium may increase the size of the hippocampus in bipolar patients by stimulating the generation of new neurons and promoting their differentiation into neuroblasts, neurons, or microglia.

Reduction of lithium induced interstitial fibrosis on co-administration with amiloride

Long-term administration of lithium is associated with chronic interstitial fibrosis that is partially reduced with exposure to amiloride. We examined potential pathways of how amiloride may reduce interstitial fibrosis. Amiloride was administered to a rat model of lithium induced interstitial fibrosis over a long term (6 months), as well as for short terms of 14 and 28 days. Kidney cortical tissue was subjected to RNA sequencing and microRNA expression analysis. Gene expression changes of interest were confirmed using immunohistochemistry on kidney tissue. Pathways identified by RNA sequencing of kidney tissue were related to ‘promoting inflammation’ for lithium and ‘reducing inflammation’ for amiloride. Validation of candidate genes found amiloride reduced inflammatory components induced by lithium including NF-κB/p65Ser536 and activated pAKTSer473, and increased p53 mediated regulatory function through increased p21 in damaged tubular epithelial cells. Amiloride also reduced the amount of Notch1 positive PDGFrβ pericytes and infiltrating CD3 cells in the interstitium. Thus, amiloride attenuates a multitude of pro-inflammatory components induced by lithium. This suggests amiloride could be repurposed as a possible anti-inflammatory, anti-fibrotic agent to prevent or reduce the development of chronic interstitial fibrosis.

Activating SIRT-1 Signalling with the Mitochondrial-CoQ10 Activator Solanesol Improves Neurobehavioral and Neurochemical Defects in Ouabain-Induced Experimental Model of Bipolar Disorder.

Bipolar disorder (BD) is a chronic mental illness characterized by mood fluctuations that range from depressive lows to manic highs. Several studies have linked the downregulation of SIRT-1 (silent mating type information regulation-2 homologs) signaling to the onset of BD and other neurological dysfunctions. This research aimed to look into the neuroprotective potential of Solanesol (SNL) in rats given ICV-Ouabain injections, focusing on its effect on SIRT-1 signaling activation in the brain. Ouabain, found in hypothalamic and medullary neurons, is an endogenous inhibitor of brain Na+/K+ ATPase. The inhibition of brain Na+/K+ ATPase by Ouabain may also result in changes in neurotransmission within the central nervous system. SNL is a Solanaceae family active phytoconstituent produced from the plant Nicotiana tabacum. SNL is used as a precursor for the production of CoQ10 (Coenzyme Q10), a powerful antioxidant and neuroprotective compound. In the current study, lithium (Li), an important mood stabilizer drug, was used as a control. This study looked at the neuroprotective potential of SNL at dosages of 40 and 80 mg/kg in ICV-OUA injections that caused BD-like neurobehavioral and neurochemical defects in Wistar rats. Wistar rats were placed into eight groups (n = 6) and administered 1 mM/0.5 µL ICV-OUA injections for three days. Neurochemical assessments were done in rat brain homogenates, CSF, and blood plasma samples at the end of the experiment protocol schedule. Long-term SNL and lithium administration have been shown to decrease the number of rearing and crossings and reduce time spent in the center, locomotor activities, and immobility time. Solansesol treatment gradually raises the amount of Na+/K+ ATPase, limiting the severity of behavioural symptoms. These findings also revealed that SNL increases the levels of SIRT-1 in CSF, blood plasma, and brain homogenate samples. Moreover, in rat brain homogenates and blood plasma samples, SNL modulates apoptotic markers such as Caspase-3, Bax (pro-apoptotic), and Bcl-2 (anti-apoptotic). Mitochondrial-ETC complex enzymes, including complex-I, II, IV, V, and CoQ10, were also restored following long-term SNL treatment. Furthermore, SNL lowered inflammatory cytokines (TNF-α, IL-1β) levels while restoring neurotransmitter levels (serotonin, dopamine, glutamate, and acetylcholine) and decreasing oxidative stress markers. Histological examinations also validated Solanesol’s protective effect. As a result, our findings suggest that SNL, as a SIRT-1 signalling activator, may be a promising therapeutic approach for BD-like neurological dysfunctions.

Beneficial effects of low-dose lithium on cognitive ability and pathological alteration of Alzheimer's disease transgenic mice model.

Lithium has been shown to delay the progression of Alzheimer's disease to reduce the prevalence of dementia. However, its narrow therapeutic index and numerous toxic effects at conventional dosage limited its long-term use to older subjects. Here, we tested the effect of low-dose lithium on cognitive impairment and pathology alterations in a mouse model of Alzheimer's disease, the amyloid precursor protein/presenilin-1 (APP/PS1) transgenic mouse. We found that both chronic and acute administration of lithium dose-dependently increased in blood and brain tissues. Long-term administration of low-dose lithium does not affect the body weight of APP/PS1 mice, but can significantly improve spatial memory of APP/PS1 mice. Pathologically, it also reduced β-amyloid plague and p-tau levels. Therefore, our results show that long-term low-dose lithium can ameliorate cognitive dysfunction and pathological alterations of Alzheimer's disease transgenic mice, and provide a theoretical basis for the further application of low-dose lithium in Alzheimer's disease clinical treatment.

The effect of long-term lithium administration on thyroid function and structure as compared with monotherapy by other mood stabilising drugs – a preliminary study

Aims: Long-term treatment with lithium in patients with bipolar disorder (BD) exerts a significant effect on thyroid structure and function. Previously, it was found that adding to lithium other mood stabilising or antidepressant drugs can also be important. The aim of this preliminary study was to compare thyroid structure and function in patients with BD receiving long-term lithium monotherapy with monotherapy using other mood stabilising drugs, such as carbamazepine, valproates or quetiapine. Method: Forty-one BD patients were studied (13 male, 28 female) aged 28–80 years. In 15, monotherapy with lithium was given; in 10 – with carbamazepine; and in 8 – with valproate and quetiapine. In all patients, the thyroid-stimulating hormone (TSH), free thyroxine (fT3) free triiodothyronine (fT4), and the antibodies against thyroid peroxidase (TPOAb), thyroglobulin (TGAb) and TSH receptors (TSHRAb) were estimated. Goiter was diagnosed when the thyroid volume exceeded 18 cm3 in women and 25 cm3 in men. Results: The groups were of similar age; however, the duration of quetiapine therapy was shorter than lithium or carbamazepine. Comparing to patients on lithium monotherapy, the median of TSH concentration was lower in patients on quetiapine, and the median of TPOAB lower in patients on valproates. The highest frequency of goiter (47%) was observed in patients receiving lithium. Conclusions: The results obtained may suggest that among the studied mood stabilisers, lithium exerts the biggest goiter-inducing effect. The differences between groups as to thyroid hormones and antibodies were not significant. The limitation of the study was a small number of studied patients.

Challenging the Negative Perception of Lithium and Optimizing Its Long-Term Administration.

The use of lithium for the prevention of recurrences in mood disorders has a 55-year history. Nowadays, lithium is universally accepted as the first-choice mood-stabilizer (MS) for maintenance treatment of bipolar disorder. In addition to its mood-stabilizing properties, lithium exerts anti-suicidal, immunomodulatory and neuroprotective action which may further substantiate its clinical usefulness. Despite these facts, the use of lithium in mood disorders has been greatly underutilized. The reasons include the introduction and promoting other MS as well as a perception of lithium as a “toxic drug” due to its side effects, mainly thyroid, renal and cognitive disturbances. The trends in lithium prescription in recent decades show relative stability or a decline at the expense of other mood-stabilizing drugs, both first generation (valproate) and second generation (olanzapine, quetiapine, lamotrigine). In this review article, the negative perception of lithium by some clinicians will be challenged. First, the data showing lithium superiority over other MS will be presented. Second, the lithium-induced side effects which can make a challenge for a more frequent application of this drug will be delineated, and their proper management described. Finally, an issue of benefits of long-term administration of lithium will be discussed, including the phenomenon of the “excellent lithium responders” (ER) as well as a subject of starting lithium prophylaxis early in the course of the illness. This review article is based on the 47-year experience with lithium therapy by the author of the article.

Curcumin (Curcuma longa Protects Against the Adverse Effect of Long Term Administration of Lithium on Cerebral and Cerebellar Cortices in Rats Histological and Immunohistochemical Study

Curcumin (Curcuma longa Protects Against the Adverse Effect of Long Term Administration of Lithium on Cerebral and Cerebellar Cortices in Rats Histological and Immunohistochemical Study

Protective effects of long-term lithium administration in a slowly progressive SMA mouse model.

In the present study we evaluated the long-term effects of lithium administration to a knock-out double transgenic mouse model (Smn-/-; SMN1A2G+/-; SMN2+/+) of Spinal Muscle Atrophy type III (SMA-III). This model is characterized by very low levels of the survival motor neuron protein, slow disease progression and motor neuron loss, which enables to detect disease-modifying effects at delayed time intervals. Lithium administration attenuates the decrease in motor activity and provides full protection from motor neuron loss occurring in SMA-III mice, throughout the disease course. In addition, lithium prevents motor neuron enlargement and motor neuron heterotopy and suppresses the occurrence of radial-like glial fibrillary acidic protein immunostaining in the ventral white matter of SMA-III mice. In SMA-III mice long-term lithium administration determines a dramatic increase of survival motor neuron protein levels in the spinal cord. These data demonstrate that long-term lithium administration during a long-lasting motor neuron disorder attenuates behavioural deficit and neuropathology. Since low level of survival motor neuron protein is bound to disease severity in SMA, the robust increase in protein level produced by lithium provides solid evidence which calls for further investigations considering lithium in the long-term treatment of spinal muscle atrophy.

Amiloride modifies the progression of lithium-induced renal interstitial fibrosis.

Long-term administration of lithium has been associated with the development of a chronic interstitial fibrosis in addition to nephrogenic diabetes insipidus (NDI). Earlier studies have demonstrated that amiloride, by blocking the epithelial sodium channel ENaC and thus preventing lithium uptake into the principal cells of the collecting ducts, can partially reverse lithium-induced NDI. However, there are no long-term studies examining whether or not amiloride also modifies the progressive chronic interstitial fibrosis and tubular atrophy often evident with long-term lithium exposure. Using an established animal model of lithium-induced chronic interstitial fibrosis, rats were treated with amiloride and lithium for 5months following 1month of exposure to lithium alone and compared with control animals and those given only lithium. In this study, the 5months of amiloride therapy partially mitigated the lithium-induced NDI and limited the further progression of lithium-induced kidney fibrosis. This improvement was associated with decreased expression of the pro-fibrotic connective tissue growth factor (CTGF), along with reduced myofibroblast infiltration and decreased collagen deposition around the distended cortical collecting ducts. This may, in part, be mediated by modifying lithium-induced alterations in β-catenin activity through its effects on GSK-3β.

Chronic lithium treatment rectifies maladaptive dopamine release in the nucleus accumbens.

Chronic lithium treatment effectively reduces behavioral phenotypes of mania in humans and rodents. The mechanisms by which lithium exerts these actions are poorly understood. Pre-clinical and clinical evidence have implicated increased mesolimbic dopamine (DA) neurotransmission with mania. We used fast-scan cyclic voltammetry to characterize changes in extracellular DA concentrations in the nucleus accumbens (NAc) core evoked by 20 and 60Hz electrical stimulation of the ventral tegmental area (VTA) in C57BL6/J mice treated either acutely or chronically with lithium. The effects of chronic lithium treatment on the availability of DA for release were assessed by depleting readily releasable DA using short inter-train intervals, or administering d-amphetamine acutely to mobilize readily releasable DA. Chronic, but not acute, lithium treatment decreased the amplitude of DA responses in the NAc following 60Hz pulse train stimulation. Neither lithium treatment altered the kinetics of DA release or reuptake. Chronic treatment did not impact the progressive reduction in the amplitude of DA responses when, using 20 or 60Hz pulse trains, the VTA was stimulated every 6s to deplete DA. Specifically, the amplitude of DA responses to 60Hz pulse trains was initially reduced compared to control mice, but by the fifth pulse train, there was no longer a treatment effect. However, chronic lithium treatment attenuated d-amphetamine-induced increases in DA responses to 20Hz pulse trains stimulation. Our data suggest that long-term administration of lithium may ameliorate mania phenotypes by normalizing the readily releasable DA pool in VTA axon terminals in the NAc. Read the Editorial Highlight for this article on Page 520.

Lithium and GSK-3β promoter gene variants influence cortical gray matter volumes in bipolar disorder.

Lithium is the mainstay for the treatment of bipolar disorder (BD) and inhibits glycogen synthase kinase-3β (GSK-3β). The less active GSK-3β promoter gene variants have been associated with less detrimental clinical features of BD. GSK-3β gene variants and lithium can influence brain gray and white matter structure in psychiatric conditions, so we studied their combined effect in BD. The aim of this study is to investigate the effects of ongoing long-term lithium treatment and GSK-3β promoter rs334558 polymorphism on regional gray matter (GM) volumes of patients with BD. GM volumes were estimated with 3.0 Tesla MRI in 150 patients affected by a major depressive episode in course of BD. Duration of lifetime lithium treatment was retrospectively assessed. Analyses were performed by searching for significant effects of lithium and rs334558 in the whole brain. The less active GSK-3β rs334558*G gene promoter variant and the long-term administration of lithium were synergistically associated with increased GM volumes in the right frontal lobe, in a large cluster encompassing the boundaries of subgenual and orbitofrontal cortex (including Brodmann areas 25, 11, and 47). Effects of lithium on GM revealed in rs334558*G carriers only, consistent with previously reported clinical effects in these genotype groups, and were proportional to the duration of treatment. Lithium and rs334558 influenced GM volumes in areas critical for the generation and control of affect, which have been widely implicated in the process of BD pathophysiology. In the light of the protective effects of lithium on white matter integrity, our results suggest that the clinical effects of lithium associate with a neurotrophic effect on the whole brain, probably mediated by GSK-3β inhibition.

Lithium and GSK3-β Promoter Gene Variants Influence White Matter Microstructure in Bipolar Disorder

Lithium is the mainstay for the treatment of bipolar disorder (BD) and inhibits glycogen synthase kinase 3-β (GSK3-β). The less active GSK3-β promoter gene variants have been associated with less detrimental clinical features of BD. GSK3-β gene variants and lithium can influence brain gray matter structure in psychiatric conditions. Diffusion tensor imaging (DTI) measures of white matter (WM) integrity showed widespred disruption of WM structure in BD. In a sample of 70 patients affected by a major depressive episode in course of BD, we investigated the effect of ongoing long-term lithium treatment and GSK3-β promoter rs334558 polymorphism on WM microstructure, using DTI and tract-based spatial statistics with threshold-free cluster enhancement. We report that the less active GSK3-β rs334558*C gene-promoter variants, and the long-term administration of the GSK3-β inhibitor lithium, were associated with increases of DTI measures of axial diffusivity (AD) in several WM fiber tracts, including corpus callosum, forceps major, anterior and posterior cingulum bundle (bilaterally including its hippocampal part), left superior and inferior longitudinal fasciculus, left inferior fronto-occipital fasciculus, left posterior thalamic radiation, bilateral superior and posterior corona radiata, and bilateral corticospinal tract. AD reflects the integrity of axons and myelin sheaths. We suggest that GSK3-β inhibition and lithium could counteract the detrimental influences of BD on WM structure, with specific benefits resulting from effects on specific WM tracts contributing to the functional integrity of the brain and involving interhemispheric, limbic, and large frontal, parietal, and fronto-occipital connections.

Nephrologische Nebenwirkungen einer Langzeittherapie mit Lithium

Lithium is widely used in the treatment of bipolar disorders. Long-term administration of lithium often leads to side effects concerning the subjects: nephrology, endocrinology and surgery. This review emphasizes nephrotoxicity.Lithium treatment may disturb responsiveness to antidiuretic hormone (ADH), causing a nephrogenic diabetes insipidus. Furthermore long-term lithium therapy may trigger hyperparathyreoidism with hypercalcemia and chronic interstitial nephritis with development of microcysts. Long-term patients have an increased risk to develop impaired renal function. Lithium-induced endstage renal disease is rare. Termination of lithium treatment may decrease the risk of progression.To ensure security of lithium treatment regular controls of urine osmolarity, lithium-, creatinine- , thyroid stimulating hormone- and calcium-levels are essential. Patients with decreased renal function should be referred to a specialist early.

Morphine sensitization as a model of mania: Comparative study of the effects of repeated lithium or carbamazepine administration

Repeated unavoidable stress induces in rats decreased reactivity to avoidable stressors and an anhedonia-like condition that are reverted by long-term antidepressant treatments and regarded as models of core symptoms of depression. Morphine-sensitized rats present resilience to stress-induced behavioral deficits and, if hyporeactivity to stress models a depressive symptom, stress resistance can be regarded as a manic symptom. This hypothesis is supported by the observation that long-term lithium administration reinstates sensitivity to stress in sensitized rats. The first aim of the study was to examine the effects of carbamazepine, a standard antimanic treatment, on the stress resilience of sensitized rats, to further characterize morphine sensitization as a model of manic symptom. Carbamazepine administration abolished stress resilience but did not interfere with the expression of sensitization. The second aim of the study was to assess whether repeated carbamazepine treatment affected the dopaminergic and behavioral responses to a natural reward, a palatable food (vanilla sugar, VS), in non food-deprived sensitized and control rats and compare these possible effects with those of repeated lithium administration. Control and sensitized rats showed increased extraneuronal dopamine levels in the nucleus accumbens shell after VS consumption and competence to acquire an instrumental VS-sustained appetitive behavior (VAB). Repeated carbamazepine treatment abolished the dopaminergic response to VS consumption and disrupted the competence to acquire VAB in control rats. Lithium-treated rats showed a dopaminergic response to VS and easily acquired the appetitive behavior. In sensitized rats, neither carbamazepine nor lithium administration interfered with the dopaminergic response to VS and the acquisition of VAB. In summary, the effect of carbamazepine on the stress resilience of sensitized rats further supported the hypothesis that morphine sensitization might model some symptoms of mania. Moreover, in control rats carbamazepine treatment elicited an anhedonia-like condition that clearly distinguished the effects of this drug from those of lithium.

Excellent lithium responders have normal cognitive functions and plasma BDNF levels

In bipolar patients, neuropsychological and biochemical disturbances persist into the remission period. Excellent lithium responders (ELRs) comprise around one third of lithium-treated patients and have total remission of recurrences on lithium monotherapy. The objective of the study was to assess the performance on neuropsychological tests and to measure brain-derived neurotrophic factor (BDNF) plasma levels in ELRs compared to patients where the effect of lithium was not optimal, and with matched healthy control subjects. The study was performed with 60 patients on prophylactic lithium treatment, 13 of whom were ELRs, and with 60 matched healthy controls. Neuropsychological tests from the CANTAB battery measuring spatial working memory and sustained attention were used. ELRs performed better on all neuropsychological tests, and had higher plasma BDNF levels than the remaining lithium patients but not different from those of healthy controls. ELRs may constitute a specific subgroup of bipolar patients in which long-term lithium administration can produce complete normality.

Involvement of AMPA receptors in the antidepressant-like effects of lithium in the mouse tail suspension test and forced swim test

In addition to its clinical antimanic effects, lithium also has efficacy in the treatment of depression. However, the mechanism by which lithium exerts its antidepressant effects is unclear. Our objective was to further characterize the effects of peripheral and central administration of lithium in mouse models of antidepressant efficacy as well as to investigate the role of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptors in these behaviors. We utilized the mouse forced swim test (FST) and tail suspension test (TST), intracerebroventricular (ICV) lithium administration, AMPA receptor inhibitors, and BS3 crosslinking followed by Western blot. Both short- and long-term administration of lithium resulted in robust antidepressant-like effects in the mouse FST and TST. Using ICV administration of lithium, we show that these effects are due to actions of lithium on the brain, rather than to peripheral effects of the drug. Both ICV and rodent chow (0.4% LiCl) administration paradigms resulted in brain lithium concentrations within the human therapeutic range. The antidepressant-like effects of lithium in the FST and TST were blocked by administration of AMPA receptor inhibitors. Additionally, administration of lithium increased the cell surface expression of GluR1 and GluR2 in the mouse hippocampus. Collectively, these data show that lithium exerts centrally mediated antidepressant-like effects in the mouse FST and TST that require AMPA receptor activation. Lithium may exert its antidepressant effects in humans through AMPA receptors, thus further supporting a role of targeting AMPA receptors as a therapeutic approach for the treatment of depression.

Myasthenia Gravis Disclosed by Lithium Carbonate

Back to table of contents Previous article Next article LETTERFull AccessMyasthenia Gravis Disclosed by Lithium CarbonateB. Alevizos M.D.S. Gatzonis M.D.,Ch. Anagnostara M.D.,B. Alevizos M.D.Search for more papers by this authorS. Gatzonis M.D.Search for more papers by this author,Ch. Anagnostara M.D.Search for more papers by this author,Published Online:1 Jul 2006AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail SIR: A patient given lithium for bipolar disorder developed severe fatigue syndrome involving only the proximal limb muscles. The clinical and laboratory assessments revealed myasthenia gravis and thymic hyperplasia. Lithium was withdrawn and the patient underwent a thymectomy. A few months later the patient’s symptoms followed a more classical myasthenic symptomatology pattern involving ocular and pharyngeal muscles. This change of the clinical manifestations may suggest that lithium modified the onset and pattern of myasthenic symptomatology. Treatment with lithium may produce muscle weakness as a transient side effect, early in the course of therapy. A severe neuromuscular junction disorder during lithium treatment has been reported in five cases. 1 – 4 Lithium caused a myasthenic syndrome in four of them, which remitted fully after lithium withdrawal. 1 – 4 One case of myasthenia gravis was unmasked by lithium and followed the typical course of the disease after lithium discontinuation. 4 We report here a similar case. Case ReportA 33-year-old man suffering from bipolar disorder since the age of 23 was referred to our clinic because of resistant depression with suicidal thoughts. A negative personal and family history for neurological, autoimmune, and psychiatric disorders was reported. Lithium (900 mg/day, levels 0.72 meq/liter) was added to his treatment as he was receiving 40 mg/day citalopram. One month later, he complained of severe generalized weakness accompanied by several occasions of collapsing suddenly during activities. He stopped working, reduced his social activities, and remained most of the time at home. This reduction of social activity was not consistent with his improved mood. While standing during examination, he suddenly collapsed in a peculiar manner reminiscent of either a factitious or a conversion symptom. However, we elicited a positive fatigue test for the arms and the legs, and a 3-minute upward gaze fixation did not elicit diplopia. A full laboratory investigation followed, confirming the diagnosis of myasthenia gravis. Thyrotropin, free and total T4 and triidothyronine were in normal range. Antibodies against Acetylcholine-receptors (AchR) were high, at 45 nmol/liter. Lithium was discontinued. The patient was started on a regimen of valproic acid (1000 mg/day) for bipolar disorder and pyridostigmine for myasthenia gravis. A computed tomography (CT) scan of the mediastinum revealed thymic enlargement, and he subsequently underwent a thymectomy. Two years later he remained under treatment with prednisolone and pyridostigmine, having attained quite normal physical activity. Attempts to reduce corticosteroids led to relapses of myasthenic symptoms such as diplopia, difficulties in mastication, swallowing, and speech.DISCUSSION In our patient the high titer of serum AchR antibodies and the presence of lymphoid hyperplasia indicate that lithium was not the causative factor per se for the production of myasthenic symptoms. The mechanism of the lithium-induced elicitation of myasthenia gravis symptoms is unclear and mainly reflects a drug’s interaction with a concurrent or underlying neuromuscular disorder, rather than impending lithium toxicity. Neil et al. 1 postulated that lithium reduces acetylcholine synthesis. There is some evidence, based on electromyographic studies that long-term lithium administration can affect neuromuscular function in a manner that becomes symptomatically most apparent during acute deviations from neurophysiologic homeostasis. 1 Lithium may produce myasthenic symptoms because of its competition for calcium inside the presynaptic motor nerve terminal, finally reducing acetylcholine (Ach)-synthesis and voltage-gated quanta release of acetylcholine. 5 In myasthenia gravis the production of nicotinic-AchR-antibodies is regulated by nicotinic-AchR-specific T helper cells. Although T-cell activation was not specifically checked, lithium may enhance T-lymphocyte activity, resulting in the worsening of a myasthenia gravis-underlying autoimmune process. 3 Other studies suggest that there is a reduced number of acetylcholine receptors in denervated muscle preparations, raising the question that lithium may selectively increase the rate of breakdown of receptors without changing the rate of synthesis. 6In our case, the development of severe fatigue followed the onset of lithium treatment fairly rapidly. The initial involvement of the proximal muscles of the shoulders and hips suggested an unusual pattern of myasthenic symptoms. However, in our case, the symptoms were modified after lithium withdrawal, to a more “typical” myasthenic clinical presentation, such as weakness of extraocular, facial and pharyngeal muscles. All of these symptoms are thought to be part of the same illness because they have a) the characteristic fluctuations of myasthenic symptoms; b) the same electrophysiological picture (in repetitive stimulation test); c) an improvement following tensilon test and oral pyridostigmine; and d) the initial symptoms persisted, albeit in more subtle manner following lithium discontinuation.ConclusionsWe suggest that this is the second reported case of myasthenia gravis with thymic hyperplasia unmasked by lithium. Our case was characterized by an initial unusual clinical pattern involving the proximal limb muscles. As lithium is widely used for the treatment of affective disorders, we believe that clinicians should keep a close watch for unusual symptoms possibly related with neuromuscular junction dysfunction.Department of Psychiatry, University of Athens, Mood Disorders Clinic, Eginition Hospital, GreeceDepartment of Neurology, University of Athens, Eginition Hospital, Greece

Chronic lithium treatment decreases tau lesions by promoting ubiquitination in a mouse model of tauopathies

Lithium, a widely used drug for treating affective disorders, is known to inhibit glycogen synthase kinase-3 (GSK-3), which is one of the major tau kinases. Thus, lithium could have therapeutic benefit in neurodegenerative tauopathies by reducing tau hyperphosphorylation. We tested this hypothesis and showed that long-term administration of lithium at relatively low therapeutic concentrations to transgenic mice that recapitulate Alzheimer's disease (AD)-like tau pathologies reduces tau lesions, primarily by promoting their ubiquitination rather than by inhibiting tau phosphorylation. These findings suggest novel mechanisms whereby lithium treatment could ameliorate tauopathies including AD. Because lithium also has been shown to reduce the burden of amyloid-beta pathologies, it is plausible that lithium could reduce the formation of both amyloid plaques and tau tangles, the two pathological hallmarks of AD, and thereby ameliorate the behavioral deficits in AD.

Erythrocyte Glutathione Levels in Lithium-Induced Hypothyroidism

Lithium, widely used in the prophylaxis of psychiatric patients with bipolar affective disorders, is well known to induce thyroid alterations. However, a possible metabolic linkage between blood thyroxine levels and its regulatory function on erythrocyte glutathione concentration has not yet been evaluated in lithium-treated patients. The aim of this study was to assess the antioxidative capacity of erythrocytes in lithium-induced hypothyroidism before and after thyroxine replacement. Thyroid ultrasound with clinical and laboratory evaluation of thyroid function and thyroid-stimulating hormone assay were performed prior to and at 6-month intervals during lithium prophylaxis in 76 patients with bipolar affective disorders. The daily lithium dosage was adjusted to 600-1200 mg and the mean duration of treatment was 2.2 +/- 0.4 years. Final assessment revealed that 12 patients had evidence of primary hypothyroidism, and these were assigned as the test group. Lithium prophylaxis was supplemented with thyroxine at a dosage of 100 mg/day within 6 months after thyroid dysfunction was diagnosed. Red blood cell superoxide dismutase activities and the glutathione contents were measured before and after thyroxine replacement. In order to assess the effect of long-term lithium administration on red blood cell glutathione and superoxide dismutase levels, 12 patients who had not developed hypothyroidism during the follow-up period were selected for the lithium-treated euthyroid group. Mann Whitney U-test and Wilcoxon rank sum W-test were used for comparison of data. A comparison of the lithium-treated test group with healthy volunteers and their own values after thyroxine replacement revealed a significant decrease in red blood cell glutathione concentrations (p = 0.000) in the hypothyroid state. However, no clinically significant changes were observed in red blood cell superoxide dismutase activities of the test group. A statistical survey also demonstrated that there was no significant difference in the thyroid-stimulating hormone values as well as the red blood cell glutathione contents or superoxide dismutase activities between healthy controls and lithium-treated euthyroid subjects. It is most likely that lithium primarily inhibited hormone production in the thyroid and that this led to a compensatory increase in thyroid-stimulating hormone secretion with a significant decrease in the red blood cell glutathione content. While the red blood cell glutathione content of hypothyroid patients was reduced to 40% of the post-thyroxine level, unchanged superoxide dismutase activity might render the erythrocytes vulnerable to oxidative stress and ultimately haemolysis. Thyroxine replacement during lithium prophylaxis of psychiatric patients is advisable in order to prevent subclinical hypothyroidism and related defects of erythrocyte antioxidant capacity.