Calcium homeostasis in long-term lithium-treated women with bipolar affective disorder

The authors investigated the effect of long-term lithium administration on intracellular calcium mobilization. The subjects were 13 women with bipolar affective disorder stabilized on lithium and 12 matched healthy controls. Total and ionized serum calcium, intracellular calcium ion concentration, plasma parathyroid hormone (PTH) and tyrotropin (TSH), serum electrolytes and cyclic AMP (cAMP) activity in platelets were measured. The serum electrolytes sodium, potassium and creatinine and plasma PTH and TSH were all within normal ranges in patients and controls and no differences were found between the two groups. No difference was found in basal and prostaglandin E1 (PGE1)-stimulated cAMP generation in platelets between patients and controls. However, total serum calcium and ionized serum calcium levels were higher in patients than in controls and there was a significant correlation between these two measures. In the patient group, serum lithium concentration correlated positively with stimulated levels of intracellular calcium in platelets. In the present study, no distinct hyperparathyroidism was found in lithium-treated patients. However, our findings indicate that lithium administration affects calcium metabolism in patients with bipolar affective disorder inducing mild hypercalcemia and a dose-dependent normalized calcium mobilization. Furthermore, our results did not support the hypothesis that lithium's primary site of action in bipolar illness may be on signal transduction mechanisms.     

Comparison between saliva and serum lithium concentrations in patients treated with lithium carbonate.

The relation between serum and saliva lithium concentration was studied in patients treated with lithium carbonate. In 23 patients a highly variable saliva/serum ratio was found in simultaneous saliva and serum samples. In five patients studied during a period of 4-8 weeks three patients showed a high fluctuation in saliva/serum lithium ratio. In 20 patients saliva lithium concentrations varied unexpectedly in a second sample produced after 15 min. Although some authors report a high and stable relation between saliva and serum lithium concentration, we consider the saliva lithium level unreliable as a prediction of the serum lithium level in patients treated with lithium carbonate.     

Renal,thyroid and parathyroid function during lithium treatment: laboratory tests in 207 people treated for 1–30 years

A total of 207 patients (diagnoses revised according to DSM-HI-R) attended our outpatient clinic and were treated with lithium for 1–30 years. They were subjected to conventional renal, thyroid and parathyroid function tests. With increasing treatment duration, the renal tests showed only moderate deviations from expected reference values. No patient developed renal insufficiency. Oversubstitution (thyrotropin ≤0.1 mU/l) was suspected in 25% of the patients on thyroxine. Cross-sectionally unrecognized hypothyroidism was found in 6% of the patients. Elevated ionized serum calcium was found in 25% and elevated serum intact parathyroid hormone in 23% of the patients.     

The profile and severity of lithium-induced side effects in mentally healthy subjects.

In a double-blind, placebo-controlled, crossover design various side effects (= unwanted effects) during 6 months of therapeutic serum lithium levels (0.7-1.1 mmol/1) to nonpsychiatric patients were studied. The side effects were measured by self-rating scales and independent observer rating scales administered every 2-4 weeks throughout the study. After months of treatment, lithium induced hand tremor and thirst/polyuria; however, without any relationship to the serum levels of lithium. The frequency of tremor was highest in patients above the age of 60 years. No initial sedative-like lithium effect was found.     

Outcome of lithium prophylaxis: a prospective follow-up of affective disorder patients assigned to high and low serum lithium levels

The purpose of the study was to examine the outcome of long-term lithium treatment in consecutively admitted affective disorder patients assigned to high and low serum lithium levels. A total of 91 patients were diagnosed according to DSM-III criteria and randomly allocated to two open treatment groups in which prophylactic lithium was administered in high (serum lithium 0.8-1.0 mmol L^-1) and low (serum lithium 0.5-0.8 mmol L^-1) doses, respectively. The patients were followed for 2 years or until discontinuation of lithium treatment or readmission to hospital for recurrence of affective illness. The main outcome of the treatment groups was compared with Kaplan-Meier survival curves and by Cox regression analysis. A total of 31 patients (34%) completed 24 months of prophylactic lithium treatment without recurrence and readmission to hospital. In total, 18 patients (20%) suffered a recurrence on lithium, and 42 patients (46%) discontinued lithium or were lost to follow-up. No effect of treatment group was seen, either for the total patient group or for the large subgroup of bipolar patients when analysed separately. A number of patients did not maintain their original assignment to the high serum lithium levels group. The results were analysed both according to assignment and according to actual serum lithium levels. Abuse of alcohol or medication was associated with a poor outcome. Only one third of the patients completed 2 years of lithium prophylaxis successfully. No difference in the protection against recurrences was observed between patients maintained on high and low serum lithium levels.     

Headache in children and dynamic thiol/disulfide balance evaluation with a new method

Headache is one of the most common causes of presentation to the physician in children. We aimed to evaluate the dynamic thiol/disulfide homeostasis with a new method in children with headache and also to investigate the relationship between the headache type, pain severity and duration in our study. We included 40 patients diagnosed with migraine, 40 patients diagnosed with tension-type headache (TTH) and 40 healthy children in the study. No significant difference was found between the total thiol, native thiol, and disulfide levels of the patient and control groups. However, the disulfide/native thiol and disulfide/total thiol ratios were higher in the migraine group than in the TTH and control groups. No correlation was found between the Pediatric Migraine Disability Assessment (PedMIDAS) score and the headache duration and any of the thiol/disulfide parameters. A negative correlation was found between the total thiol and native thiol levels and the PedMIDAS score in the TTH group. Migraine and TTH patients have different effect to thiol/disulfide homeostasis.     

Delirium syndrome as a side-effect of lithium in normal lithium levels

Lithium is used with great success in the treatment of manic patients and for prophylaxis of bipolar disorders. There are only few reports about neuropsychiatric side effects at therapeutic serum levels. We report on a 38 year old woman with bipolar disorder who was treated with lithium for 20 years without side-effects. Subsequent to a manic episode, she became disoriented at night and showed marked memory deficits. The patient did not show any neurological or gastrointestinal signs of intoxication. Lithium serum-levels were in therapeutic range. The psychiatric symptoms disappeared when lithium was stopped. We interpret these symptoms as delirant syndrome with pseudo-dementia at therapeutic lithium serum levels. This side-effect must be taken into account even in patients on successful longtime lithium therapy.     

Effects of lithium on the kidney

We tested kidney function in 268 patients given lithium treatment for an average period of 37.6 months and in 59 manic-depressive patients never given lithium. No patients suffered serious renal damage during the course of our observations. Maximum concentration capacity was lower and serum creatinine concentration higher in the lithium treated patients than in the controls, but the differences did not achieve statistical significance. Females had poorer concentrating ability than males, both among the control subjects and during lithium treatment. Concomitant antipsychotic drug therapy may affect concentrating ability and possibly glomerular function adversely.     

The electrophysiological effects of lithium in the rat.

The effects of lithium on the tail nerve conduction velocity of the rat were studied. No effect of lithium on the conduction velocity was found, even at toxic serum lithium levels. No effect of lithium on repetitive stimulation of the distal forelimb flexor muscles was seen. The results suggest that electrophysiological measurements do not provide an effective means of titrating serum lithium levels in the rat. The results may have clinical signficance since they provide evidence against neuropathic or neuromuscular transmission defects as the cause of the transient weakness of some patients taking lithium.     

Lithium use in octogenarians

OBJECTIVES: To assess the tolerability and side-effect profile of lithium use in a group of octogenarians attending a specialized lithium clinic. METHODS: This is a cross-sectional study looking at all patients of eighty years and over attending a lithium clinic. Charts were examined to assess renal function, thyroid function and level of side-effects during their course of lithium treatment in order to assess the tolerability of this medication in octogenarians. RESULTS: Twelve patients of 80 years and over (with an average age of 83.6 years) were taking lithium for an average period of 53.7 months. They had a mean serum level of 0.42 mmol/l. No patient had to discontinue lithium therapy because of side-effects, even though some patients did develop transient abnormalities of renal function. One patient developed diabetes insipidus. One female patient developed hypothyroidism. CONCLUSIONS: Lithium was well tolerated and was administered safely to this cohort of octogenarians. Monitoring of serum lithium levels and kidney and thyroid function should preferably be done in the setting of a specialized lithium clinic.     

Lithium kinetics in single daily dosing

The feasibility of single daily dosing of lithium carbonate was tested in eight recurrent manic-depressives being treated with lithium prophylaxis. The patients received their entire 24-h maintenance dose at 8:00 p.m. for 12 consecutive days. The suitability of single daily dosing was determined by comparing 1) lithium through levels; 2) lithium kinetic parameters of half-life, clearance, and volume of distribution; and 3) renal function parameters of serum creatinine, creatinine clearance, and mean 24-h urine output during the initial divided daily dosage trial and the subsequent single daily dosage trial. The observation of no significant changes in either serum half-lives or renal lithium clearance levels supports the conclusion that the average steady-state lithium serum concentration (Cpss) is unchanged by conversion to single daily doses. No significant changes were observed in either serum creatinine or creatinine clearance. However, a significant decrease in the 24-h urine output was noted on the single daily dose.     

Renal clearance technic for individualizing lithium dosage in routine hospital care

Lithium has a narrow therapeutic index and exhibits a wide pharmacokinetic variability. Individual dosage regimen adjustment is necessary to warrant the efficacy and safety of long-term treatment. We propose the "renal clearance method" for rapid determination of the lithium carbonate daily dose for chronic therapy. After the first intake of drug by a manic-depressive patient, a four-hour trial is performed. It involves two blood samplings and two urine collections, in which lithium and creatine are assayed. Comparison of observed creatinine with a value predicted according to age, morphological characteristics, sex and serum creatinine of the patients allows the interpretation of conflicting results. The estimation of lithium and creatinine clearances of each patient is performed using a computerized or manual method which unfolds a decision procedure. The daily dosage (1.5 to 6 250 mg tablets in two or three daily intakes) is deduced from the according lithium renal clearance (0.4 to over 2 l/h) by means of a nomogram established in previous studies on about 50 patients. The clearance method has been investigated in routine hospital care on a 40 patients sample. The range of satisfactory lithium serum levels during patients monitoring was 0.6-0.9 mmol/l. Accurate dosage regimen forecasting is obtained in 92% of the patients. The percentage observed in a subset of 13 patients with the C24 method, which relies on a unique blood sample 24 hours after the first dose, was much lower (54%). The renal clearance method appears as a robust and reliable technique for individual lithium dosage regimen adjustment in routine care.     

Erythrocyte lithium efflux in bipolar patients and control subjects: the question of reproducibility

The reproducibility of in vitro erythrocyte lithium efflux and lithium efflux in the presence of selected membrane transport inhibitors (phloretin, ouabain, 4,4'-diisothiocyano-2,2'-disulphonic acid stilbene, and p-chloromercury-benzene sulphonate) was investigated in bipolar patients and age- and sex-matched control subjects. Efflux experiments were repeated three times in each patient-control pair within a period of 14 days. No differences were detected between patients and control subjects in any of the parameters measured. All components of lithium efflux showed wide day-to-day variation in the same subject in both patients and control subjects. Intersubject variability, however, was significantly greater than intrasubject variation. Since intraindividual variation of phloretin-inhibited lithium efflux was found to be considerable, and no real patient-control differences could be detected, the significance of this in vitro parameter in bipolar affective illness seems somewhat questionable and should be carefully reconsidered. The relevance of these findings to the putative cell membrane dysfunction in this disease is discussed.     

Lithium-induced delirium with therapeutic serum lithium levels: a case report.

Lithium-induced delirium occurring in geriatric patients with serum lithium levels that are within the "therapeutic" range (less than 1.5 mEq/L) has been described in the literature. We present a case that illustrates three major issues regarding this syndrome: (1) differentiating lithium-induced delirium from a recurrence of a chronic psychiatric disorder; (2) the use of the electroencephalogram in supporting this diagnosis; and (3) factors that may increase a patient's vulnerability to delirium while on lithium. A brief review of the most relevant literature is then presented. We conclude that lithium-induced neurotoxicity should be suspected in any patient receiving lithium who develops delirium, regardless of the serum level, and that immediate discontinuation of the medication be considered.     

Lithium and peripheral nervous system function in manic-depressive patients

Introduction — Lithium salts are widely used in treatment of affective disorders, but lithium may cause electrophysiologically detectable changes in peripheral nervous system even with lithium concentrations within recommended therapeutic limits. The risk of lithium treatment against other risks to peripheral nervous system in psychiatric patients with affective psychoses was tested in our study. Material and method — Electrophysiologic parameters of motor and sensory peripheral nerve fibre function were measured in two age-matched groups of psychiatric patients (20 lithium-treated and 20 affective psychotic patients without lithium treatment) and a group of 20 healthy age-matched volunteers. Results — Lower amplitudes of M waves (p < 0.015) and sensory nerve action potentials (p < 0.020) on stimulation of the median nerve have been found in both groups of patients. On peroneal nerve stimulation lower M wave amplitudes have been found only in the group of lithium-treated patients (p < 0.055). No significant differences in conduction parameters of motor and sensory fibres were demonstrated. Conclusion — Our results demonstrate subclinical involvement of motor and sensory axons in affective-psychotic patients, which is only slightly more pronounced in lithium-treated patients. We suggest that lithium (within therapeutic plasma concentrations) is just one among the factors leading towards minor axonopathy in psychiatric patients.     

Method for prediction of serum lithium levels

A new computer-assisted method for predicting lithium levels and consulting dosage of lithium is demonstrated. The method is based on a mathematical model describing elimination of lithium after lithium treatment of any duration and regularity. From two values of serum concentration of lithium obtained during a single day, parameters of the model are computed and used for prediction. In an evaluation study involving 20 inpatients, the results demonstrated a high correlation between predicted and observed levels (r = 0.80) and revealed no systematic error of prediction. The elimination rate of lithium in these patients was unrelated to age or to duration of previous lithium therapy.     

Drug-drug interactions as a determinant of elevated lithium serum levels in daily clinical practice

OBJECTIVE: Lithium is a drug with a narrow therapeutic window. Concomitantly used medication is a potentially influencing factor of lithium serum concentrations. We conducted a multicentre retrospective case-control study with the aim of investigating lithium-related drug interactions as determinants of elevated lithium serum levels in daily clinical practice. METHODS: Cases were patients with an increase of at least 50% in lithium serum concentrations resulting in an elevated lithium serum level of at least 1.3 mmol/L, and who were not suspected of a suicide attempt. Controls were patients who showed stable lithium serum levels within the therapeutic range. Use and start of non-steroidal anti-inflammatory drugs, diuretics, renin-angiotensin inhibitors, theophyllin and antibiotics were investigated as potential determinants of the elevated lithium serum levels. Irregularity in lithium dispensing pattern, change in lithium dosing regimen, age, gender, prescribing physician and laboratory parameters were investigated as potential confounders. RESULTS: We included 51 cases and 51 controls in our study. Five (9.8%) controls and 15 (29.4%) cases used potentially interacting co-medication [OR of 3.83 (95%CI 1.28-11.48)]. Start of potentially interacting co-medication was observed in eight (15.7%) cases and in zero (0%) controls resulting in an OR of 20.13 (95% CI 1.13-359). After adjustment for co-medication, irregularity in lithium dispensing pattern, change in lithium dosing regimen, and age, the statistically significant association was lost. We report an OR of 2.70 (95% CI 0.78-9.31) for use of concomitant medication, with a large contribution of antibiotic agents, and an OR of 3.14 (95% CI 1.15-8.61) for irregularity in lithium dispensing pattern. CONCLUSION: Use of co-medication, especially antibiotics, tends to be associated with elevated lithium serum levels.     

Deanol, lithium and placebo in the treatment of tardive dyskinesia. A double-blind crossover study.

A double-blind crossover study on the effects of deanol and lithium carbonate was conducted on a sample of 29 chronic schizophrenic patients with tardive dyskinesia. In addition to his usual treatment with different neuroleptics, each patient received during an 8-week period either deanol, lithium carbonate or placebo. A 4-week wash-out period was inserted between each of the 8-week periods of experimental treatment of the tardive dyskinesia. The administration of either deanol, lithium carbonate or placebo added to the neuroleptic treatment did not produce a statistically significant improvement of tardive dyskinesia in our patient population as a whole. Favorable and unfavorable responses are discussed.     

Renal function of patients in long-term treatment with lithium citrate alone or in combination with neuroleptics and antidepressant drugs

Renal function was studied in patients given lithium citrate alone or in combination with neuroleptics or tricyclic antidepressants or both. No other drugs were given. None of the groups given lithium citrate with other drugs had lithium ion clearances that differed significantly from the groups given lithium citrate alone, nor was there any difference in the clearances of sodium, potassium, or creatinine between these groups. The 24-hour urine volume of patients receiving antidepressant drugs was similar to that of the patients receiving lithium citrate monotherapy but was significantly higher in patients given neuroleptics. The increase in urine volume could not be ascribed to alterations in glomerular filtration rate or proximal tubular resorption but could be accounted for entirely by lowered resorption of water in the distal tubules. We concluded that no change of lithium citrate dose is required when patients so treated are given additional neuroleptic or tricyclic antidepressant drugs.     

A study on visual evoked responses in children with chronic renal failure.

AIMS OF THE STUDY: Nervous involvement is frequent in patients with renal failure. Early recognition of the condition by electrophysiological tests may provide means for protective measures before irreversible damage of nervous system (NS) structures takes place. This study has two objectives: (1) examining whether pattern-reversal visual evoked potential (PR-VEP) studies may provide information relating to possible subclinical NS involvement in pediatric patients with chronic renal failure (CRF) and (2) looking for a possible relationship between serum parathormone (PTH) and creatinine levels and PR-VEP parameters. METHODS: PR-VEP recordings at low spatial frequencies were performed and peak-to-peak amplitudes and latencies of the P100 component were measured in 19 neurologically asymptomatic children with CRF, 15 of whom were on continuous ambulatory peritoneal dialysis (CAPD) and four on hemodialysis (HD). A similar procedure was applied to 29 healthy, age- and sex-matched, subjects. Patients were sub-grouped according to the serum PTH and creatinine levels. Student's-t and one-way ANOVA tests were used for comparisons within patient and control groups and sub-groups relating to serum PTH and creatinine levels. RESULTS: We did not demonstrate any statistically significant differences in PR-VEP parameters in patients vs. controls. PR-VEP amplitudes were higher in patients with low serum creatinine levels as compared to group with high creatinine values and to controls. No other relationship was found between PR-VEP parameters and serum PTH and creatinine levels in this pediatric population. CONCLUSION: Young patients with CRF and under dialysis do not necessarily show pathologic alterations in PR-VEPs when they are neurologically intact. This fact suggests that either PR-VEPs are not sensitive enough to detect clinically silent NS involvements in such patients, or it could be related to positive effects of the currently improving standards in the management of dialysis and supportive nutrition. Additional factors such as the age of the patient during examination, the latency between dialysis and visual evoked potential (VEP) assessment, or the selected check size may have some impact on the results and justify further studies.