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PubMed2001

Discontinuation of lithium augmentation in an elderly cohort.

OBJECTIVES: To observe the effects of gradual discontinuation of lithium augmentation therapy in a group of patients over the age of 65 years and to measure the rate of relapse and to identify any factors which would predict relapse. METHODS: This was a naturalistic study involving 21 patients who were on lithium augmentation and whose lithium was discontinued for a variety of clinical reasons. In most cases lithium was tapered and discontinued over a period of 2-12 weeks. Demographic and other variables were collected at baseline and compared between those who remained well and those that subsequently relapsed. RESULTS: Eleven patients (52.4%) relapsed following discontinuation of lithium augmentation. Those who relapsed had been on lithium for significantly longer than those who remained well off lithium (p = 0.007). There was a trend towards more hospital admissions in the relapse group (p = 0.062). CONCLUSIONS: When lithium augmentation therapy is discontinued in elderly depressives over half of these patients relapse. A longer duration of prediscontinuation lithium treatment and more hospital admissions appear to be associated with increased risk of relapse.

Aged↗
PubMed1996

Lithium and neuroleptics in combination: is there enhancement of neurotoxicity leading to permanent sequelae?

Neurotoxicity in relation to concomitant administration of lithium and neuroleptic drugs, particularly haloperidol, has been an ongoing issue. This study examined whether use of lithium with neuroleptic drugs enhances neurotoxicity leading to permanent sequelae. The Spontaneous Reporting System database of the United States Food and Drug Administration and extant literature were reviewed for spectrum cases of lithium/neuroleptic neurotoxicity. Groups taking lithium alone (Li), lithium/haloperidol (LiHal) and lithium/ nonhaloperidol neuroleptics (LiNeuro), each paired for recovery and sequelae, were established for 237 cases. Statistical analyses included pairwise comparisons of lithium levels using the Wilcoxon Rank Sum procedure and logistic regression to analyze the relationship between independent variables and development of sequelae. The Li and Li-Neuro groups showed significant statistical differences in median lithium levels between recovery and sequelae pairs, whereas the LiHal pair did not differ significantly. Lithium level was associated with sequelae development overall and within the Li and LiNeuro groups; no such association was evident in the LiHal group. On multivariable logistic regression analysis, lithium level and taking lithium/haloperidol were significant factors in the development of sequelae, with multiple possibly confounding factors (e.g., age, sex) not statistically significant. Multivariable logistic regression analyses with neuroleptic dose as five discrete dose ranges or actual dose did not show an association between development of sequelae and dose. Database limitations notwithstanding, the lack of apparent impact of serum lithium level on the development of sequelae in patients treated with haloperidol contrasts notably with results in the Li and LiNeuro groups. These findings may suggest a possible effect of pharmacodynamic factors in lithium/neuroleptic combination therapy.

Adult↗
PubMed1985

Bronchorelaxing activity of lithium in vitro.

The potential value of lithium as a bronchodilator has been evaluated by in vitro methods using guinea pig tracheal spirals and lung parenchymal strips. The use of twin spirals and strips prepared by splitting the tissues longitudinally into two equal halves has been used to minimize animal variations. The cumulative concentration-effect relationships of isoproterenol have been determined on these twin tissues contracted submaximally with histamine. The responses of the twin tissues did not significantly differ. The cumulative concentration-effect relationships of lithium on guinea pig tracheal spirals and lung parenchymal strips have been evaluated and compared with those of isoproterenol. Lithium showed a dose-dependent relaxation on both tissues. However, the potency of lithium to produce a relaxant effect was significantly lower than isoproterenol. The relaxing effect of lithium on parenchyma was significantly higher than that on the trachea. The lithium-induced inhibitory effect on the contractile responses of tracheal spirals and lung parenchymal strips to histamine before and after incubating the tissues with lithium for 15 min has been determined. Lithium significantly reduced the contractile effect of histamine on both tissues. These findings suggest a potential clinical applicability of lithium for treating airway hyperresponsiveness.

Animals↗
PubMed1982

Teratogenic effects of lithium in mice.

The question of the teratogenicity of lithium carbonate was tested in two inbred strains of mice that are susceptible to teratogens. Strains 129 and A/J mice were treated with varying dosages of lithium carbonate on day 8, 9, or 10, and strain A/J mice were sequentially treated on days 11, 12, and 13 of gestation. Another group of mice of strain 129 were given lithium carbonate in drinking water throughout pregnancy. Levels of lithium were determined in mouse serum (and in brain) of mothers and their offspring with the purpose of comparing equivalent values in mice and in man. A baseline dosage of 0.8 mg of lithium carbonate was chosen, since this dose produced a serum lithium level of 0.8 meq/L, which is comparable to values of patients treated for manic-depressive illness. This baseline dosage or 2 and 4 times this amount did not prove teratogenic in strain 129 mice. However, 5.0 mg (200 mg/kg), which is one-half the LD50 value, caused 41% malformations. The baseline dosage did not cause malformations in strain A/J when given on day 11, 12, or 13 of gestation. Lithium carbonate given in the drinking water to strain 129 mice throughout pregnancy at a concentration that produces serum levels in mice consistent with human values was deleterious. The data suggest that whole or part of total litters were eliminated. The few survivors were apparently normal. Our results suggest that 6 times the therapeutic serum lithium level in humans is teratogenic in mice, as tested by acute experiments. Chronic treatment with a quantity of lithium that produces a serum level equivalent to that of human values is toxic to whole or part of the litters of mice.

Animals↗
PubMed2000

Lithium's effects on rat liver glucose metabolism in vivo.

Oral administration of lithium carbonate to fed-healthy rats strongly decreased liver glycogen content, despite the simultaneous activation of glycogen synthase and the inactivation of glycogen phosphorylase. The effect seemed to be related to a decrease in glucose 6-phosphate concentration and to a decrease in glucokinase activity. Moreover, in these animals lithium markedly decreased liver fructose 2,6-bisphosphate, which could be a consequence of the fall in glucose 6-phosphate and of the inactivation of 6-phosphofructo-2-kinase. Liver pyruvate kinase activity and blood insulin also decreased after lithium administration. Lower doses of lithium carbonate had less intense effects. Lithium administration to starved-healthy and fed-streptozotocin-diabetic rats caused a slight increase in blood insulin, which was simultaneous with increases in liver glycogen, glucose 6-phosphate, and fructose 2, 6-phosphate. Glucokinase, 6-phosphofructo-2-kinase, and pyruvate kinase activities also increased after lithium administration in starved-healthy and fed-diabetic rats. Lithium treatment activated glycogen synthase and inactivated glycogen phosphorylase in a manner similar to that observed in fed-healthy rats. Glycemia was not modified in any group of animals. These results indicate that lithium acts on liver glycogen metabolism in vivo in at least two different ways: one related to changes in insulinemia, and the other related to the direct action of lithium on the activity of some key enzymes of liver glucose metabolism.

Animals↗
PubMed2002

Lithium ameliorates HIV-gp120-mediated neurotoxicity.

To investigate the protective effects of lithium against HIV-gp120-mediated toxicity in vivo, mice were exposed to lithium and gp120 and levels of the neuronal markers, microtubule-associated protein-2 and NeuN, and the astrocyte marker, glial fibrillary acidic protein, were determined. In addition, SH-SY5Y neuronal cells exposed to gp120 and lithium were assessed for cell viability. Lithium pretreatment protected the hippocampus of mice from gp120-mediated toxicity. Similarly, preexposure of neuronal cultures to lithium significantly reduced gp120-associated neurotoxicity. However, posttreatment with lithium had minimal neuroprotective effects against gp120, both in vivo and in vitro. The protective effects of lithium in vitro were blocked by LY294002, an inhibitor of the phosphatidylinositol 3-kinase/Akt pathway. Taken together, these results demonstrate that lithium might be neuroprotective against gp120-mediated toxicity and suggest that prophylactic treatment with lithium may prevent the onset/progression of HIV-associated cognitive impairments.

AIDS Dementia Complex↗
PubMed1986

The enhancement by lithium of the 5-HT1A mediated serotonin syndrome produced by 8-OH-DPAT in the rat: evidence for a post-synaptic mechanism.

Administration of lithium chloride (10 mmol/kg on day 1 and 3 mmol/kg twice daily on subsequent days, SC) for 3-14 days enhances the components of the serotonin syndrome produced by 8-hydroxy-2-(di-propylamino)tetralin (8-OH-DPAT) in the rat. The hypothermic response produced simultaneously was unaltered. Following lithium administration for 3 days the motor response to 5-methoxy,N,N-dimethyltryptamine was also facilitated. These data suggest that lithium administration enhances post-synaptic 5-HT receptor-mediated behavioural responses. (-)-Propranolol (20 mg/kg, IP) but not (+)-propranolol (20 mg/kg IP) fully antagonised the facilitated response to 8-OH-DPAT seen following lithium administration; ritanserin (200 micrograms/kg, IP) was without effect. These findings favour a mechanism for the action of lithium involving the 5-HT1A receptor. Depletion of 5-hydroxytryptamine (5-HT) with parachlorophenylalanine (PCPA, 300 mg/kg, IP on day 1 and 2 of lithium administration) did not prevent the facilitation by lithium of the response to 8-OH-DPAT. These data strengthen the suggestion that lithium has its effect on 5-HT1A-mediated motor function by a post-synaptic action. By contrast, motor responses to the putative 5-HT1B receptor agonist 5-methoxy-3-(1,2,3,6-tetrahydro-pyridin-4-yl)-1H-indole (RU 24969) were unaltered by repeated lithium administration.

5-Hydroxytryptophan↗
PubMed1988

Effects of lithium on synaptosomal Ca2+ fluxes.

Lithium is the primary treatment for mania, and it has been employed as a therapeutic agent in the treatment of a number of other conditions. In spite of its widespread clinical use, the specific mechanism by which lithium acts is still not known. Because lithium bears some chemical resemblance to Ca2+ and because it has been found to interfere with many Ca2+-dependent processes, we investigated the possibility that lithium can alter intracellular Ca2+ homeostasis by an effect on Ca2+ fluxes. When added in vitro to synaptosomes prepared from rat forebrains, lithium had no effect on 45Ca2+ influx mediated by fast or slow phase depolarization-dependent Ca2+ channels or by Na+/Ca2+ exchange. In vitro treatment with lithium also had no effect on ATP-dependent Ca2+ sequestration by mitochondria or synaptosomal endoplasmic reticulum. In contrast, 45Ca2+ influx in synaptosomes prepared from rats treated chronically with lithium was increased significantly relative to controls. The fact that chronic in vivo treatment with lithium affected synaptosomal Ca2+ flux whereas in vitro treatment did not is consistent with the time course of therapeutic effectiveness in man. The results suggest that lithium does not directly interact with synaptosomal Ca2+ flux, but rather may influence Ca2+ flux through an indirect mechanism following chronic treatment.

Animals↗
PubMed1984

The effects of chronic lithium on behavioral and biochemical indices of dopamine receptor supersensitivity in the rat.

The effects of dietary lithium on several indices of dopamine receptor supersensitivity were examined in rats during withdrawal from chronic administration of haloperidol. Chronic haloperidol enhanced the locomotor stimulant action of d-amphetamine, and this effect was attenuated by lithium. In contrast, lithium did not affect the amphetamine response in animals that had not previously received haloperidol. Apomorphine-induced hypothermia was not influenced by the chronic haloperidol treatment. On the other hand, during withdrawal from chronic haloperidol, spontaneous locomotor activity (20 h) and apomorphine-induced stereotypy were increased, but neither of these effects was attenuated by lithium. In addition, lithium did not affect the chronic haloperidol-induced increase in 3H-spiperone binding sites in the striatum. Lithium alone had no effect on any of these measures except for causing a slight prolongation of the hypothermic effect of apomorphine. The results indicate that not all DA-receptor-mediated responses are enhanced by chronic administration of neuroleptics (e.g., apomorphine-induced hypothermia). In addition, while lithium reduces the effects of chronic haloperidol administration on d-amphetamine-induced locomotor activity, this is not because lithium prevents haloperidol-induced supersensitivity of postsynaptic DA receptors because more direct measures of this phenomenon (e.g., 3H-spiperone binding, apomorphine-induced stereotypy) are not affected by lithium.

Animals↗
PubMed2003

The effects of lithium on cognition: an updated review.

RATIONALE: Adverse cognitive effects associated with lithium are often implicated as contributing to vocational and social impairment, as well as medication noncompliance. As impaired cognitive functioning caused by lithium has clear clinical implications, it is important to determine whether evidence for or against impaired cognitive functioning exists in the literature. OBJECTIVES: An attempt is made to synthesize findings from previous studies, which assess a variety of cognitive domains, to determine whether conclusions can be drawn regarding lithium-associated cognitive impairment. The "reversibility" of neuropsychological impairment following lithium discontinuation and whether lithium administration has negative cumulative effects on cognition were also reviewed. METHODS: Key word searches on "Medline" and "Psych Info" were completed for clinical articles that investigated the neuropsychological effects of lithium in clinical and normal populations between 1968 and 2000. RESULTS: Despite methodological flaws, poor replicability and the subtle cognitive effects of lithium, five consistent findings emerged from the review; impairment on tasks of psychomotor speed, impaired functioning in the majority of studies examining verbal memory, no impairment on tasks of visuo-spatial constructional ability or attention/ concentration, and no negative cumulative effect. CONCLUSIONS: Many patients administered lithium carbonate complained of mental slowness. Lithium carbonate also appeared to have definite, yet subtle, negative effects on psychomotor speed. Studies reviewed also showed a trend toward impaired verbal memory. Recommendations with respect to future research, methodological and statistical problems, and additional clinical implications are presented.

Antidepressive Agents↗
PubMed2001

Chronic lithium treatment increases the expression of brain-derived neurotrophic factor in the rat brain.

RATIONALE: Lithium is the most widely prescribed mood stabilizer, but the precise mechanism of lithium is unresolved. OBJECTIVE: We examine the effects of the administration of therapeutically relevant concentrations of lithium on the expression of brain-derived neurotrophic factor (BDNF) and its receptor, Trk B, as well as glia-derived neurotrophic factor (GDNF) and its receptors, RET and GDNFR-alpha, in the rat brain. In addition, we also examined the effect of another well-prescribed mood stabilizer, valproate, on the expression of BDNF and GDNF. METHODS: Rats were kept on a 0.2% lithium carbonate-containing diet for 1, 7, 14, or 28 days or treated with valproate (400 mg/kg per day i.p.) for 1 or 14 days. After the brains were rapidly removed, the levels of BDNF, GDNF, and their receptors were measured by ELISA or western blot analysis. RESULTS: Chronic lithium treatment for 14 and 28 days significantly increased the expression of BDNF in the hippocampus and temporal cortex. In addition, chronic lithium treatment for 14 days significantly increased the expression of BDNF in the frontal cortex. In contrast, acute or chronic dietary lithium treatment did not alter GDNF expression in these brain regions. In addition, acute or chronic lithium treatments did not change the levels of Trk B, RET, or GDNFR-alpha immunoreactivity. As well as lithium, repeated administration of valproate also increased the expression of BDNF in the frontal cortex and hippocampus. CONCLUSIONS: Our results suggest that the chronic administration of mood stabilizers may produce a neurotrophic effect mediated by the upregulation of BDNF in the rat brain.

Administration, Oral↗
PubMed1994

Clinical manifestations and management of acute lithium intoxication.

Acute lithium intoxication is a frequent complication of chronic lithium therapy for manic depressive disorders. Because of lithium's narrow therapeutic index and widespread use, lithium intoxication remains prevalent in 1994. This review summarizes information on the renal handling of lithium and the physiologic basis for toxicity. Recent reports that describe previously unrecognized side effects of lithium intoxication are discussed. We also present management guidelines based upon our understanding of the renal handling of lithium. In this review we compare the effectiveness of lithium removal by various dialysis methods, including bicarbonate dialysis, peritoneal dialysis and continuous arteriovenous hemofiltration. Hemodialysis remains the cornerstone for the treatment of acute lithium toxicity.

Acute Disease↗
PubMed1986

Perfusion with lithium modifies neurophysiological responses in the CA1 region of the hippocampal slice preparation.

The effects of acute lithium exposure on extracellular electrophysiological responses in the CA1 region of the in vitro hippocampus were investigated. Field potentials were assessed while perfusing slices with normal media or media in which LiCl was substituted for NaCl in 30, 20, 10 and 2 mM amounts. Lithium concentration in the slice following 20 min perfusion with 20 mM lithium was determined to be about 14 mM. At the higher concentrations, lithium exposure depressed the presynaptic fiber volley and antidromic population spike. On the other hand, the population EPSP and orthodromic population spike were enhanced. No significant changes were found at 2 mM. The findings are compatible with one action of lithium being on the excitability of axons and synaptic terminals. Comparisons were drawn between previous studies involving chronic lithium exposure and the present results. In this acute preparation lithium effects, as reflected in the population EPSP, were in opposition to those found with chronic lithium exposure. Changes demonstrated in this preparation in fiber volley and antidromic population spike paralleled those found with chronic lithium exposure.

Action Potentials↗
PubMed1991

Lithium transport in the mouse brain.

Using the stable isotopes of lithium 6Li and 7Li, and the nuclear reaction 6Li(n,alpha)3H for detection, we have studied the isotopic exchange of lithium in various areas of the mouse brain and in the mouse plasma, under conditions of constant concentration of total lithium. The neutron irradiations were performed using 'cold' neutrons, at the European Institute Von Laue-Langevin. The nuclear reaction track densities were determined using an automatic image analyser. In the plasma, the isotopic ratios, 6Li/7Li, were measured using 'Secondary Ion Mass Spectrometry'. The concentration of total lithium in the plasma was kept close to 0.28 mM. The brain concentration of total lithium (referred to the tissue water content) ranged from more than 2 mM in the thalamus to less than 0.65 mM in the white matter of the cerebellum. The Nernst potential of lithium thus ranged from approx. -50 to approx. -20 mV, which means that lithium is probably not far from electrochemical equilibrium between brain cells and plasma. At any moment, the isotopic abundance of 6Li (ratio of 6Li to total lithium) in the different brain areas, were not significantly different from one another. The time-course of the isotopic abundance of 6Li in the brain was fitted by the composition of two exponential terms. The time-course of the isotopic abundance of 6Li in the plasma was also fitted by the composition of two exponential terms. These analytic curves (for the brain and for the plasma) were not significantly different from each other, at the precision of the measurements. This means that the isotopic equilibration of lithium between brain and plasma is almost instantaneous (i.e. accomplished in a few min at the most).

Animals↗
PubMed1988

Fewer metabolites of dietary choline reach the blood of rats after treatment with lithium.

Choline is an important precursor for the biosynthesis of acetylcholine, phosphatidylcholine and sphingomyelin. It is also a major source of labile methyl groups. Lithium is an important component of the treatment of bipolar affective illness, and it inhibits choline transport across membranes. We studied the effect of lithium treatment upon the appearance in blood, liver and intestine of metabolites formed from dietary choline. Rats were treated for 9 days with 2 mEq/kg lithium carbonate or water. Animals were fasted overnight, and on the 10th day were fed with a solution containing radiolabeled choline chloride. The lithium-treated groups also received 2.0 mEq/kg lithium as part of this solution. After an oral dose of 1 ml of a 1 mM choline solution, the lithium-treated animals had significantly lower levels of choline-derived radiolabel in blood than did controls at 30, 60, 120, and 180 minutes (47% (+/- 5%; SEM), 51% (+/- 7%), 59% (+/- 4%) and 74% (+/- 9%), respectively). We observed similar decreases of the accumulation in blood, at 180 minutes after the dose, of choline-derived radiolabel when choline was administered at lower or higher concentrations. After an oral treatment containing 0.1, 1 or 10 mM choline, lithium treated animals accumulated 69% (+/- 6%; SEM), 66% (+/- 11%) and 72% (+/- 7%) as much radiolabel in serum as did controls. Most of the radiolabel found in blood at 180 minutes was in metabolites of choline which are formed within liver (betaine and phosphatidylcholine). The diminished accumulation of radiolabel in serum after lithium treatment was not due to increased accumulation of label by erythrocytes, liver or gut wall. We suggest that lithium influences the release by liver of betaine and phosphatidylcholine.

Animals↗
PubMed1982

Behavioral and biochemical changes induced by lithium and L-tryptophan in muricidal rats.

Lithium (0.5--12 meq/kg) and L-tryptophan (100--800 mg/kg) inhibited the muricidal (mouse killing) response in isolated, male, Long Evans rats and did so both in an acute (single dose) and on an longer-term intraperitoneal treatment basis. The response was dose-dependent. There was no concomitant motor impairment at doses effective in inhibiting the muricidal response. Plasma lithium levels were positively correlated with the percentage inhibition of muricidal behavior. When lithium and L-tryptophan were administered in combination in their smallest effective doses, the behavioral interaction was synergistic in the acute and addictive in the longer-term treatment. The effects of pharmacological treatment on the inhibition of muricidal behavior were: lithium and L-tryptophan greater than L-tryptophan greater than - lithium. The results of biochemical assays showed that these compounds fore- and hindbrain serotonin turnover. The biochemical action of lithium and L-tryptophan in combination on brain serotonergic pathways was again clearly more potent than that which occurred after treatment with either lithium or L-tryptophan alone. The magnitude of the biochemical changes paralleled those of psychopharmacological changes. These data show an interaction between lithium and L-tryptophan both in the repression of aggressive behavior in rats and in the alteration of centrally acting serotonergic function. These data further elucidate a mechanism of action through central serotonergic function for a psychotherapeutic agent, lithium, and for aggressive behavior, muricide.

Aggression↗
PubMed1991

Effects of lithium and desimipramine on second messenger responses in rat hippocampus: relation to G protein effects.

The effects of chronic administration of lithium, short-term administration of lithium, chronic administration of DMI and a combination of short-term administration of lithium and chronic administration of DMI on second messenger responses were studied in the hippocampus of the rat. Lithium reduced the ability of carbachol to inhibit forskolin-stimulated activity of adenylate cyclase in hippocampal membranes but had no effect on carbachol-stimulated formation of inositol phosphate in hippocampal slices. Lithium, however, reduced the degree of stimulation of formation of inositol phosphate, induced by noradrenaline. Desimipramine alone did not affect carbachol- or noradrenaline-mediated reactions and a combination of short-term administration of lithium and chronic administration of DMI did not potentiate the action of lithium on adenylate cyclase. Both lithium and DMI abolished the inhibition by 5-HT of carbachol-stimulated formation of inositol phosphate a 5-HT1A receptor-mediated response. It is concluded that the chronic effects of administration of lithium may be related to actions at the G protein level and that different modes of coupling of receptors to G proteins may be responsible for the variety of effects observed.

Adenylyl Cyclases↗
PubMed1996

A novel action of lithium: stimulation of glutamate release and inositol 1,4,5 trisphosphate accumulation via activation of the N-methyl D-aspartate receptor in monkey and mouse cerebral cortex slices.

Beginning at therapeutic concentrations (1-1.5mM), the anti-manic-depressive drug, lithium, stimulated the release of the major excitatory central neurotransmitter, glutamate, in monkey cerebral cortex slices in a time- and concentration-dependent manner, and this was associated with increased inositol 1,4,5-trisphosphate [Ins(1,4,5)P3] accumulation. (+/-)-3-(2-Carboxypiperazin-4-yl)-propyl-1-phosphoric acid (CPP), dizocilpine (MK-801), ketamine, and Mg(2+)-antagonists to the N-methyl D-aspartate (NMDA) receptor/channel complex selectivity inhibited lithium-stimulated Ins(1,4,5)P3 accumulation. Antagonists to cholinergic-muscarinic, alpha 1-adrenergic, 5-HT2-serotoninergic and H1-histaminergic receptors had no effect. Antagonists to non-NMDA glutamate receptors had no effect on lithium-stimulated Ins(1,4,5)P3 accumulation. Possible reasons for this are discussed. Similar results were obtained in mouse cerebral cortex slices. Carbetapentane, which inhibits glutamate release, inhibited lithium-induced Ins(1,4,5)P3 accumulation in this model. It is concluded that the primary effect of lithium in the cerebral cortex slice model is stimulation of glutamate release, which, via activation of the NMDA receptor, leads to Ca2+ entry. Ca2+ entry, in turn, activates phospholipase C. These effects may have relevance to the therapeutic action of lithium in the treatment of manic-depression, as well as its toxic effects, especially at lithium blood levels above 1.5mM. A general conclusion which can be drawn from these studies and earlier studies in our laboratory is that lithium potentiates the action of phospholipase C, whether this enzyme is activated by lithium-induced presynaptic release of neurotransmitter, such as glutamate, or by the addition of an exogenous neurotransmitter, such as acetylcholine. However, this does not appear to be due to a direct activation of phospholipase C.

Animals↗