Lithium transport in human fibroblasts: relationship to RBC lithium transport and psychiatric diagnoses

Cultured fibroblasts were prepared from six normal controls, five DSM-III manic patients, and six DSM-III schizophrenic patients. Lithium (Li+) uptake, 24-hour Li+ ratios, and steady-state membrane potential were measured in these cell lines. The uptake of 10 mM Li+ reached maximum at 2 hours, with an intracellular concentration of approximately 15 mM. No significant difference in uptake was found among subject groups. Twenty-four hour Li+ (ratio of intracellular/extracellular Li+) ratios were determined by incubating the cell lines for 24 hours in the presence of 2 mM Li+. No significant difference was observed among groups; nor was there any significant correlation between the fibroblast 24-hour ratios and 24-hour in vitro ratios determined in donor red cells. The relationship between membrane potential and the 24 hour Li+ ratio in fibroblasts was determined. The average potential in these cell lines was -56 mV and was not affected by Li+ treatment. No correlation between the Li+ ratio and membrane potential was found.     

The effects of lithium carbonate on serum gastrin in psychiatric patients

Indications that gastrin is produced in the pancreatic A₁ cells and that there is a lithium-related increase in A₁ cell nuclei in guinea pigs are background factors leading up to this study. The effect of lithium treatment on the gastrin level in serum was tested on four patients with different psychiatric diagnoses. All the patients showed normal serum values during the first 3 weeks of the treatment period. Possible reasons for the relatively unelevated levels of serum gastrin (non-detectable to 300 pg gastrin/ml serum) are discussed. The effects of catecholamines on gastrin release is also mentioned as a lead in the study of the relationships between lithium, amines, gastrin and carbohydrate metabolism.     

Measurement of tissue lithium concentration by lithium magnetic resonance spectroscopy in patients with bipolar disorder

Measurements of the lithium concentration in the occipital pole of the head and calf muscle of nine patients with bipolar disorder in remission were performed using in vivo lithium-7 nuclear magnetic resonance spectroscopy (7Li NMR). 7Li NMR measurements were performed on a 1-m-bore, 1.85-T, superconducting magnet supplemented with a multinuclear spectrometer, using 11.5-cm-diameter surface coils. The average lithium concentration in the occipital pole was 0.36 +/- 0.10 mEq/L, whereas in the muscle it was 0.50 +/- 0.17 mEq/L, both lower than the average serum lithium concentration (0.79 +/- 0.23 mEq/L). The average brain/serum lithium concentration ratio was 0.47 +/- 0.12 whereas the average muscle/serum lithium concentration ratio was 0.66 +/- 0.20. There was a positive correlation between the brain versus serum and brain versus muscle lithium concentrations. The hypothesis is advanced that the minimal effective concentration of brain lithium concentration for maintenance treatment of bipolar disorder is around 0.2-0.3 mEq/L.     

Recovery of erythrocyte Li/Na countertransport and choline transport from lithium therapy

Li⁺/Na⁺ countertransport, choline transport, and intracellular Li⁺ and choline were measured in the RBC of a manic-depressive subject as a function of time after termination of Li⁺ therapy. Countertransport recovered from its inhibition by Li⁺ in 10 days. This recovery involved a decrease in the Michaelis-Menten parameter K_m, without change in V_max. RBC choline decreased, and choline influx rose, much more slowly back towards pre-Li⁺ values over the course of two months. Thus, choline transport was still inhibited long after Li⁺ levels in RBC and plasma had become undetectable. Measurements on age-separated RBC fractions showed that recovery of choline transport was mainly in the young-cell fraction. Hence inhibition of choline transport by Li⁺ may be irreversible at the level of the individual RBC.     

Postpartum mania in bipolar manic-depressive patients withdrawn from lithium carbonate.

Three women, previously diagnosed as bipolar I manic-depressive, were withdrawn from lithium carbonate prophylaxis immediately prior to their pregnancies. The patients had been euthymic while on lithium carbonate for at least 3 1/2 years prior to their pregnancies. Two of the three patients developed a manic syndrome within 2 weeks postpartum. The use of lithium carbonate during pregnancy, and particularly in the postpartum period, requires reassessment. We advocate an ongoing clinical relationship and the reinstitution of lithium in the third trimester in most cases.     

NMR chemistry analysis of red blood cell constituents in normal subjects and lithium-treated psychiatric patients

Red blood cells from 18 lithium carbonate-treated patients with bipolar affective disorder and 12 normal volunteers were analyzed using 1H-nuclear magnetic resonance (NMR) spectroscopy. The spectra were analyzed for alanine, adenosine triphosphate (ATP), choline, 2,3-diphosphoglycerol, glucose, glutathione, glycine, and lactate. Significant elevations of choline and lactate were found in the lithium-treated patients compared with normal, unmedicated subjects. The elevation of lactate due to anaerobic metabolism in the red blood cells was further investigated via fluorometric analysis and appears to be caused by blood standing at room temperature. The observed increases in red blood cell choline are sufficiently high and statistically significant to warrant additional studies on the dramatic effects of lithium on this red cell metabolite, which might be important for an understanding of its mechanism of action in psychiatric disorders.     

Combined haloperidol and lithium carbonate in treating manic patients

In view of the recent discussion concerning the safety of combined therapy with haloperidol and lithium carbonate,^1,2 we wish to present our experience with 28 patients who received this combination of drugs for the treatment of acute mania.     

A comparison of purposeless movements in psychiatric patients treated with antipsychotic drugs, and normal individuals.

Oro-facial dyskinesia and purposeless trunk and limb movements were assessed, using a standard videotape rating technique, in 182 psychiatric patients receiving antipsychotic medication, in a second sample of 43 elderly psychiatric patients also receiving antipsychotic drugs, and 85 normal, drug-naive subjects. In both the first patient sample and the group of normal subjects, oro-facial dyskinesia was more common over 50 years of age. Statistical analysis of the data suggested that drug-induced oro-facial dyskinesia has a characteristic pattern of movement distribution significantly different from that of idiopathic oro-facial dyskinesia. The videotapes of the first patient sample and the normal subjects were viewed by a neurologist who assessed and categorised all movements. Purposeless trunk and limb movements were classified as either normal or abnormal. Normal purposeless movements were significantly more common in the drug-naive subjects. The presence of abnormal movements such as choreiform movements, dystonias and stereotypies and mannerisms was limited, almost exclusively, to the patients.     

Elevation of RBC glycine and choline levels in geriatric patients treated with lithium

During 6 weeks of lithium treatment, the RBC glycine and choline levels of five cognitively impaired geriatric subjects without affective disorders increased significantly and correlated with RBC and plasma lithium levels. The subjects' cognitive processes did not improve.     

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.     

Growth hormone (GH) release following thyrotropin-releasing hormone (TRH) injection in manic patients receiving lithium carbonate

(1) The effect of intravenous injection of synthetic TRH (500 μg) on the plasma GH was investigated in six patients in the manic state and five normal volunteers, both before and during lithium treatment, for 3–4 weeks. (2) TRH caused a significant increase in plasma GH in four out of six manic patients during lithium treatment. (3) TRH only raised plasma GH in one patient before lithium treatment. (4) No appreciable change was noted in normal subjects either before or during lithium treatment. (5) The positive GH responses to TRH in manic patients on lithium were observed 90–120 min after TRH except for one patient. (6) The delayed GH response may be caused by secondary effects of TRH on brain monoamine neurotransmitters, rather than by a direct action of TRH on the pituitary.     

Brain lithium concentration by 7Li- and 1H-magnetic resonance spectroscopy in bipolar disorder.

A method was developed to measure lithium concentrations in the human brain using in vivo 7Li- and 1H-magnetic resonance spectroscopy (MRS). Lithium concentrations measured by MRS in 10 lithium-treated bipolar patients were at the half level of those measured in serum. Serial measurements indicated that lithium concentrations in the brain increased markedly during manic episodes, while serum concentrations were unchanged. These findings suggest that in vivo measurements of lithium concentrations in the brain, combined with measurements of concentrations in serum, may be useful in monitoring the effects of therapeutic drugs.     

Expression of ataxin-7 in CNS and non-CNS tissue of normal and SCA7 individuals

Spinocerebellar ataxia type 7 (SCA7) is a neurodegenerative disorder primarily affecting the cerebellum, brain stem and retina. The disease is caused by an expanded polyglutamine tract in the protein ataxin-7. In this study we analyzed the expression pattern of ataxin-7 in CNS and non-CNS tissue from three SCA7 patients and age-matched controls. SCA7 is a rare autosomal dominant disorder, limiting the number of patients available for analysis. We therefore compiled data on ataxin-7 expression from all SCA7 patients (n=5) and controls (n=7) published to date, and compared with the results obtained in this study. Expression of ataxin-7 was found in neurons throughout the CNS and was highly abundant in Purkinje cells of the cerebellum, in regions of the hippocampus and in cerebral cortex. Ataxin-7 expression was not restricted to regions of pathology, and there were no apparent regional differences in ataxin-7 expression patterns between patients and controls. The subcellular distribution of ataxin-7 was primarily nuclear in all brain regions studied. In cerebellar Purkinje cells, however, differences in subcellular distribution of ataxin-7 were observed between patients and controls of different ages. Here we provide an increased understanding of the distribution of ataxin-7, and the possible implication of subcellular localization of this protein on disease pathology is discussed.