Lithium attenuates dopamine depleting effects of reserpine and tetrabenazine but not that of alpha methyl-p-tyrosine

Concurrent administration of lithium (Li) significantly attenuates the dopamine (DA) depleting effects of reserpine and tetrabenazine, but does not change alpha-methyl-p-tyrosine (AMPT) induced DA depletion in rat brain. This effect of Li is probably mediated, in part, by inhibiting the magnesium-dependent binding of both reserpine and tetrabenazine to their specific receptor sites. Such interaction between these drugs may attenuate the beneficial effects of tetrabenazine and reserpine on patients with tardive dyskinesia or tardive dystonia who are treated concurrently with lithium for their psychiatric disorder.     

Chronic ethanol inhibits inositol metabolism in specific brain regions

Many neurotransmitters and hormones in the nervous system transmit signals through receptors coupled to the poly-phosphoinositide (PI) signaling pathway. In this study, an in vivo protocol with [3H]inositol was used to examine the effect of chronic ethanol administration on inositol metabolism and poly-PI turnover in the cerebral cortex, hippocampus, and cerebellum of mouse brain. C57BL/6 mice were given a nutritionally complete liquid diet containing either ethanol (5%, w/v) or isocaloric sucrose for 2 months. Mice were injected intracerebrally with [3H]inositol; after 16 or 24 hr, they were injected intraperitoneally with lithium (8 mEq/kg body weight) to inhibit the inositol monophosphatase (IP1) activity. All mice were decapitated 4 hr after lithium injection. Labeled inositol phospholipids accounted for 16 to 23% of total labeled inositol in different regions of control mouse brain, and the percentages in the hippocampus were consistently higher than the cerebral cortex and cerebellum. In control mice, the percentages of labeled IP1 after a 4-hr lithium treatment were 11.5%, 9.9%, and 3.7% for cerebral cortex, hippocampus, and cerebellum, respectively. Chronic ethanol feeding resulted in a significant (p < 0.05) decrease in the percent of labeled IP1 and inositol phospholipids, and this effect was observed in the cerebral cortex and, to a lesser extent, hippocampus but not cerebellum. When ratios of labeled IP1 were expressed against labeled inositol phospholipids as an index of the poly-PI turnover activity, significant decreases in IP/lipid ratios were observed in the cerebral cortex, but not the hippocampus or cerebellum. Although mice killed 24 + 4 hr after the last ethanol feeding would have experienced an 8-hr period of ethanol withdrawal, compared with the 16 + 4-hr group, no differences in IP/lipid ratios were observed between the two time groups. These results illustrate regional differences in the effect of chronic ethanol on inositol metabolism in the brain, but no difference in poly-PI turnover in brain due to ethanol withdrawal.     

Disruption by lithium of phosphoinositide signalling in cerebellar granule cells in primary culture

Mild depolarisation (20 mM KCl) synergistically enhances the ability of a muscarinic agonist to activate phosphoinositide turnover and to elevate inositol 1,4,5-trisphosphate [Ins(1,4,5)P3] in cerebellar granule cells in primary culture. The effects of lithium on this intense stimulation of phosphoinositide turnover was studied. Lithium causes depletion of cytoplasmic inositol and phosphoinositides, which results in the inhibition of phosphoinositide turnover within 15 min and the return of Ins(1,4,5)P3 to basal levels at this time. This inhibition could not be reversed by culturing and preincubating cerebellar granule cells in concentrations of inositol similar to those detected in the CSF. Inositol concentrations substantially in excess of those in the CSF not only reversed the effects of lithium on stimulated Ins(1,4,5)P3 levels, but significantly enhanced this level in comparison with stimulation in the absence of lithium. sn-1,2-Diacylglycerol elevation during stimulated phosphoinositide turnover was also disrupted by lithium, but in contrast to Ins(1,4,5)3, the presence of lithium resulted in a transient enhancement of the elevation evoked by carbachol plus mild KCl depolarisation, which was reversed by 500 microM inositol, but not by 200 microM inositol. The implications of these phenomena in relation to the mechanism of action of lithium in the treatment of manic depression are discussed.     

Effects of chronic lithium and electroconvulsive stimuli on cholecystokinin mRNA expression in the rat brain

This study compares the effect of lithium (Li+) and electroconvulsive stimuli (ECS), two treatments commonly used in the treatment of affective disorders, on CCK mRNA expression in the rat brain. Two groups of rats receiving either 4 week Li+ or vehicle food supplementation and two groups receiving 6 ECS or 6 sham ECS during 2 weeks were studied. A significant decrease in CCK mRNA levels was seen in the caudate putamen both after Li+ as compared to vehicle and ECS as compared to sham ECS, 27 and 25%, respectively. A small (10%), yet significant, decrease was also seen in the inner entorhinal cortex after Li+. The results indicate that both Li+ and ECS inhibit CCK synthesis in the caudate putamen and are consistent with other findings of presumed decreased dopaminergic action in this part of the brain following these treatments.     

Lithium enhances muscarinic receptor-stimulated CDP-diacylglycerol formation in inositol-depleted SK-N-SH neuroblastoma cells

The psychotherapeutic action of Li+ in brain has been proposed to result from the depletion of cellular inositol secondary to its block of inositol monophosphatase. This action is thought to slow phosphoinositide resynthesis, thereby attenuating stimulated phosphoinositidase-mediated signal transduction in affected cells. In the present study, the effect of Li+ on muscarinic receptor-stimulated formation of the immediate precursor of phosphatidylinositol, CDP-diacylglycerol (CDP-DAG), has been examined in human SK-N-SH neuroblastoma cells that have been cultured under conditions that alter the cellular content of myo-inositol. Resting neuroblastoma cells, like brain cells in vivo, were found to concentrate inositol from the culture medium, achieving an intracellular level of 60.0 +/- 4 nmol/mg of protein. The addition of carbachol to [3H]cytidine-prelabeled cells elicited a four- to fivefold increase in the accumulation of labeled CDP-DAG. This stimulated formation of [3H]CDP-DAG was completely blocked by the addition of 10 microM atropine, was not dependent on the presence of Li+, nor was it affected by co-incubation with myo-inositol. This result was in sharp contrast to findings in rat brain slices, in which carbachol-stimulated formation of [3H]CDP-DAG was potentiated approximately 10-fold by Li+ and substantially reduced by coincubation with inositol. The formation of [3H]CDP-DAG in labeled SK-N-SH cells by carbachol was both concentration and time dependent. The order of efficacy of muscarinic ligands in stimulating [3H]-CDP-DAG accumulation paralleled that established in these cells for inositol phosphate accumulation, i.e., carbachol > or = oxotremorine-M > bethanecol > or = arecoline > oxotremorine > pilocarpine.(ABSTRACT TRUNCATED AT 250 WORDS)     

Results of long-term (over 10 years) lithium therapy

The effectiveness of long term lithium prophylaxis has been studied in thirty patients with bipolar affective disorder. The study covered only these patients receiving prophylactic lithium treatment for at least 10 years, who demonstrated positive response to lithium during the initial five years of the therapy. Standard medical documentation was analyzed for the time-course of the illness within the whole observation period (number, duration and character of remissions) as well as for the history of lithium therapy (serum lithium concentrations, regularity of medical checks, breaks in the lithium treatment). The effectiveness of lithium prophylaxis has been found to diminish with time in as many as 40% of patients subjected to the prolonged lithium therapy, as evidenced by an increased number of recurrences in this group. The explanation for this phenomenon is not clear, particularly that the change in the responsiveness to lithium has been found not to correlate with age, duration of illness, duration of lithium therapy, incidence of somatic diseases and history of lithium treatment (serum lithium concentrations, breaks in the treatment).     

Effects of short-and long-term administration of tricyclic antidepressants and lithium on norepinephrine turnover in brain

The findings summarized in this paper show that norepinephrine turnover in brain is decreased after acute administration of imipramine or desmethylimipramine but tends to increase during chronic administration of these tricyclic antidepressants. Similarly, it appears that there also may be important differences between the effects of acute and chronic administration of lithium salts on norepinephrine turnover in the central nervous system. Such changes in norepinephrine turnover that develop gradually over the course of long-term drug administration may help to explain the need for chronic administration of tricyclic antidepressants or lithium salts in the treatment of patients with affective disorders.     

Indications, adverse effects and complications of lithium therapy

The application of lithium preparations in the therapy and prophylaxis of recidivations of affective psychoses has essentially gathered in point in psychiatry during the last years. Apart from the discussion of the indication, the contraindication and efficacy especially concomitant appearances, side effects and dangers as well as their influencibility are demonstrated, the knowledge of which is of importance also for the physician not dealing with psychiatry.     

Prediction of the lithium ratio in man by means of an in vitro test

The movement of the lithium ion (Li+) across the membrane of intact erythrocytes incubated in vitro was assessed under two different experimental conditions in which such transfer occurred primarily due to the activity of a lithium-sodium countertransport system. The 13 subjects on whom the in vitro procedures were done subsequently received lithium carbonate for 14 to 56 days, and the extent of accumulation of Li+ by erythrocytes in vivo was measured. While both in vitro procedures yielded data that correlated with the extent of accumulation of Li+ by erythrocytes in vivo, a system measuring the efflux of Li+ from Li+-loaded cells produced a much higher correlation (0.976). The magnitude of this correlation suggests that this in vitro system can be used for further investigations into the relevance of the erythrocyte accumulation of Li+ to the pathogenesis and treatment of affective disorders.     

The distribution of lithium between erythrocytes and plasma: in vitro studies on the transport of lithium in human erythrocytes

Distribution ratiors of intracellular lithium (Lii) and extracellular Li (Lie) were determined in vitro after incubation of Li-free or Li-loaded red cells in media containing varying Li-concentrations (37 degrees C, pH 7.4). The distribution ratios Lii/Lie obtained in vitro after 24 h of incubation corresponded to those found in vivo. The results indicate that Li can be extruded from red cells against an electrochemical gradient. This Li extrusion is inhibited by replacing extracellular Na+ with K+ or choline+, but is not affected by ouabain or by glucose depletion.     

Augmentation of valproate with lithium in a case of rapid cycling affective disorder

Rapid cycling affective disorder is characteristically unresponsive to conventional interventions. In bipolar rapid cycling affective disorder, the manic episodes may be controlled with either neuroleptics or electroconvulsive therapy, but the depressive episodes are highly intractable. This report describes the successful treatment of a patient with a bipolar rapid cycling affective disorder using a combination of valproic acid and lithium carbonate.     

Synaptic defects and compensatory regulation of inositol metabolism in inositol polyphosphate 1-phosphatase mutants

Phosphoinositides function as important second messengers in a wide range of cellular processes. Inositol polyphosphate 1-phosphatase (IPP) is an enzyme essential for the hydrolysis of the 1-phosphate from either Ins(1,4)P2 or Ins(1,3,4)P3. This enzyme is Li+ sensitive, and is one of the proposed targets of Li+ therapy in manic-depressive illness. Drosophila ipp mutants accumulate IP2 in their system and are incapable of metabolizing exogenous Ins(1,4)P2. Notably, ipp mutants demonstrate compensatory upregulation of an alternative branch in the inositol-phosphate metabolism tree, thus providing a means of ensuring continued availability of inositol. We demonstrate that ipp mutants have a defect in synaptic transmission resulting from a dramatic increase in the probability of vesicle release at larval neuromuscular junctions. We also show that Li+ phenocopies this effect in wild-type synapses. Together, these results support a role for phosphoinositides in synaptic vesicle function in vivo and mechanistically question the "lithium hypothesis."     

Labial herpes in patients with affective disorders receiving long-term lithium carbonate

Lithium carbonate has been administered to 69 patients (45 women and 24 men) for 1-17 years as affective disorders prevention. Its effect on the recurrence and clinical course of labial herpes infection has been analysed both prior to and after the administration of lithium carbonate. Labial herpes has been diagnosed in 28 patients before lithium prophylaxis. The drug significantly decreased virus infection recurrence incidence in this group. No labial herpes recurrence has been noted in 13 patients after the treatment. Lithium efficiency has not been dependent on patients' age, duration of therapy, and lithium levels in both blood serum and erythrocytes. These results suggest, that lithium salts may be effective in certain herpes simplex infections at doses used for prevention affective disorders.     

Relationship between dopamine agonist stimulation of inositol phosphate formation and cytidine diphosphate-diacylglycerol accumulation in brain slices

Dopamine receptor-coupled stimulation of inositol phosphate formation has been characterized extensively, but little is known about the diacylglycerol arm of this dual-signaling pathway. This study examined several parameters of cytidine diphosphate-diacylglycerol (CDP-DG) accumulation as an index of agonist-stimulated DG formation. Rat brain slices pre-labeled with 5-[3H]cytidine were incubated with various test agents in the presence of LiCl and accumulated CDP-DG analyzed. Dopamine and SKF38393 significantly and dose-dependently stimulated CDP-DG accumulation. SKF38393 responses were inhibited by neomycin and reversed by myo-inositol or by exclusion of LiCl. Compared to inositol phosphate formation in 2-[3H]inositol-prelabeled slices, the CDP-DG responses were proportionately greater, while the agonist EC50 values were similar between the two assays. The D1-receptor antagonist SCH23390 inhibited SKF38393-mediated responses at 0.1-10 microM concentrations, whereas greater concentrations reversed the inhibition. SKF38393 effects were completely blocked by the DG kinase inhibitor R59022, thus precluding any role for phospholipase-D or de novo phosphatidate synthesis in the dopaminergic response. D609 which inhibits phosphatidylcholine-specific phospholipase-C (PLC), potently inhibited both CDP-DG accumulation and inositol phosphate formation. These findings demonstrate that the selective D1-receptor antagonist SCH23390 is a partial agonist at the D1-like dopamine receptor that couples to phosphoinositide signaling, that dopaminergic facilitation of phosphoinositide signaling is independent of de novo phosphatidate synthesis, and that the widely used enzyme inhibitor, D-609, is probably not selective for phosphatidylcholine-specific PLC in brain slice preparations. The greater sensitivity of the CDP-DG measurement presents this assay as a reliable and possibly superior index of dopamine receptor-coupled PLC activation in intact tissues.     

Chorea caused by lithium intoxication: a case report and literature review

We report a patient who developed an acute, reversible, generalized choreiform disorder from lithium (Li) intoxication. This medication was prescribed for manic-depressive disorder, and serum levels became elevated after the addition of a diuretic for the treatment of hypertension. There were no other apparent causes for the movement disorder, and it was associated with other known features of Li intoxication, including ataxia and encephalopathy. There was a delay between the initial symptoms of Li intoxication and the onset of chorea. The chorea improved as serum Li levels diminished, with some lag time. This represents the eleventh case report of Li-induced chorea, but only the sixth in a patient without concomitant neuroleptic therapy, and the first presented with videotape confirmation. A review of these other cases is included, and possible mechanisms are discussed.     

Coping with Ottoman Turkish Genocide: an exploration of the experience of Armenian survivors

1. The relationship between lithium (Li) side effects and brain Li concentration was examined in 17 patients with bipolar disorder treated with Li and other psychotropic drugs. 2. Brain Li concentration was measured by Li-7 magnetic resonance spectroscopy (MRS). Side effects were assessed using the UCLA General Side Effect Rating Scale For Lithium Treatment (GSE). 3. There was no correlation between the total GSE score and the brain, serum, or erythrocyte Li concentrations. Patients with hand tremor had significantly higher brain Li level (0.51 + or - 0.27 mM) than those without apparent tremor (0.36 + or - 0.20 mM), but no significant difference in serum Li level was seen. As far as the patients had hand tremor, they rarely had brain Li concentration less than the therapeutic range (1 of 15 measurement). On the other hand, they often had brain Li levels less than the therapeutic range when they did not have apparent tremor (13 of 52 measurements). 4. This preliminary study suggests that hand tremor is associated with the brain Li concentration.     

Relationship between prophylactic effect of lithium therapy and family history of affective disorders

Lithium therapy response and age of onset (AOO) were studied in 98 patients with bipolar affective disorder (BPAD) who were divided into subgroups depending on type of family history of affective disorders. The highest (33.0 years) and lowest (25.5 years) age of onset were found in nonfamilial patients and in familial patients with a first-degree relative of BPAD, respectively. Nonfamilial patients showed the best response to lithium. There were 0.9 episodes/year off lithium compared to 0.3 episodes/year on lithium (an 88% decrease). A poorer response (a 71% decrease; a reduction from 1.39 episodes per year off lithium to 0.65 on lithium) was found in familial patients with a first-degree relative of BPAD. Differences in serum lithium values between the groups could not explain the observed differences. Thus, familial patients showed a more severe manifestation of the disease with an earlier AOO and a lower prophylactic effect of lithium.     

Effects of chronic lithium and carbamazepine treatment on G-protein subunit expression in rat cerebral cortex

Although lithium and carbamazepine (CBZ) are effective in the treatment of bipolar affective disorder, their mechanism of action is still unknown. Recent evidence suggests that lithium and CBZ might exert their therapeutic effects by modulating the function of guanosine triphosphate (GTP)-regulatory (G) proteins associated with central nervous system second messenger systems. In the present study, we showed that chronic lithium administration decreases G alpha s, G alpha i1, and G alpha i2 messenger RNA (mRNA) abundance by 25%-30% in rat cerebral cortex. However, the levels of G alpha s, G alpha i1, and G alpha i2 mRNA were unaffected by chronic CBZ treatment. The effects of lithium on G alpha s, G alpha i1, and G alpha i2 mRNA levels appear to be selective, as the mRNA levels of G alpha o, G alpha x, G beta 1, G beta 2, and G beta 3 subunits remained unchanged. Two days after terminating chronic lithium treatment, changes in G alpha s, G alpha i1, and G alpha i2 mRNA levels were not demonstrable. Short-term administration of lithium (2 days), however, reduced only the G alpha i2 mRNA levels. Surprisingly, there was no significant difference in the amount of immunologically detectable G alpha s-s, G alpha s-1, G alpha i(1 + 2), G alpha 0, and G beta (1 + 2) in the cortex of rats chronically treated with lithium or CBZ, compared with controls.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacokinetic interactions and side effects resulting from concomitant administration of lithium and divalproex sodium

BACKGROUND: Valproic acid is added to the lithium regimens of many patients with bipolar disorder, especially those with mania refractory to lithium treatment. METHOD: We evaluated the pharmacokinetic effects and safety of coadministration of lithium and valproate in 16 healthy volunteers in this randomized, placebo-controlled, two-period (12 days each) crossover trial. Valproate or placebo was given twice daily. On Days 6-10, lithium was added. Blood samples drawn on Days 5 and 10 were analyzed for valproate by high-pressure liquid chromatography (HPLC) and for lithium by atomic absorption spectrophotometry. RESULTS: Lithium pharmacokinetics were unchanged by valproate, but valproate C(max), C(min), and AUC rose slightly during lithium coadministration. Adverse events did not change significantly. CONCLUSION: Concomitant administration of lithium and valproate appears to be safe in patients with bipolar disorder.     

The effect of lithium on calcium-induced changes in adrenocorticotrophin levels

The calcium receptor (CaR) plays a central role in calcium (Ca) sensing by the parathyroid gland and other organs, including the brain. Chronic lithium (Li) therapy causes a significant alteration in Ca-sensing by the CaR-expressing parathyroid chief cells through an unknown mechanism, shifting the PTH set-point (the level of Ca that half-maximally suppresses PTH secretion) to the right. Ca is known to stimulate ACTH levels in normal subjects, and baseline ACTH levels are increased in patients with bipolar disorder. Because the stimulation of ACTH secretion by Ca likely involves the CaR, the aim of this study was to investigate the effects of Li on Ca-induced changes in ACTH levels, using Ca and citrate infusions in seven Li-treated patients and seven controls. During the Ca infusion, increments in serum-ionized Ca concentration (Ca(i)) were accompanied by increments in ACTH levels that were significantly greater in the Li-treated group, P = 0.014, by ANOVA. Also, cortisol levels increased significantly in the Li-treated, but not the control group, during the Ca infusion, P < 0.0001. There was a statistically significant shift in the midpoint of the Ca(i)/ACTH curve, to the right, in the Li-treated group, compared with the controls (P = 0.042), that was largely caused by an effect of Li on Ca(i). However, for comparable levels of Ca(i), there were no significant differences in the levels of ACTH between the two groups. Therefore, within the physiological range of Ca, there was no effect of Li on Ca(i)-induced change in ACTH levels.