Lithium concentration in the muscle compartment of manic-depressive patients during lithium therapy.

Pharmacokinetic (PK) techniques were used to study the effect of lithium (Li+) on Li+ fluxes and concentrations in body compartments of manic-depressives. Patients not yet on Li+ therapy were similar to normal controls in all parameters. Comparison of patients before and during chronic Li+ therapy showed no effect of Li+ therapy on intestinal absorption and renal excretion of Li+. The calculated erythrocyte (RBC)-to-plasma Li+ concentration ratio increased with Li+ therapy, as already known from direct measurements. The calculated muscle-to-plasma Li+ concentration ratio was 6-8 times higher than the RBC ratio, and increased from 1.8 to 4.2 with Li+ therapy. The higher Li+ concentration in human muscle compared to RBC is attributed to muscle's higher inside-negative resting potential, and may underlie side effects that arise in muscle from Li+ therapy. The discrepancy between the observed muscle-to-plasma ratio and that predicted for a passively distributed ion is attributed to extrusion by a countertransport process, and the increase in the observed ratio with Li+ therapy is attributed to inhibition of countertransport, as already established for RBC. Since muscle resembles nerve as an excitable cell, muscle Li+ warrants evaluation as a predictor of therapeutic response and side effects during Li+ therapy.

Neuropsychiatric disturbances associated with idiopathic calcification of the basal ganglia.

A patient with idiopathic calcification of the basal ganglia (ICBG) manifested a schizophrenialike psychosis beginning at age 17 and later developed a complex movement disorder and mild dementia. Extensive calcification of the basal ganglia was demonstrated by computerized tomography. Review of reported cases of ICBG suggests that patients who become symptomatic early in adulthood are more likely to present with psychosis, whereas those presenting later in life typically manifest dementia and a motor system disorder. ICBG, like other conditions affecting subcortical structures, can produce schizophrenialike symptoms that may precede the onset of intellectual deterioration and extrapyramidal motor disturbances.

Mutism: loss of neocortical and limbic vocalization.

A patient with complete mutism of 5 years duration was studied to determine the cause of the defective phonation. The patient had neurological findings indicative of pseudobulbar palsy, but he had lost emotional vocalization and emotional facial expression, as well as propositional speech. Phylogenetic, ontogenetic, and anatomic evidence indicates that propositional speech and volitional facial movements are mediated by corticobulbar tracts descending from neocortical areas, whereas emotional vocalization and emotional facial expression are dependent on intact limbic system connections. The findings suggest that the patient's impaired faciovocal expression was the result of lesions involving both limbic system and descending neocortical connections.

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 Km, without change in Vmax. 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.

Changes in blood plasma osmolality and states of mania.

Manic patients were studied systematically over a period of months. Fluctuations in their blood plasma osmolality were observed and these correlated significantly of and inversely with undulations in their mania rating scores. Successful treatment of patients with lithium carbonate was correlated with increasing levels of their plasma osmolality and with a significant remission of mania symptomatology. Animal studies have shown that adaptations to altered blood plasma osmolalities are accompanied by profound metabolic changes in tissues of the central nervous system. A similar relationship is likely to exist in man. We suggest, therefore, than an altered plasma osmolality is linked to changes in manic symptomatology, through osmotically regulated metabolic changes in the central nervous system.

Erythrocyte choline concentrations are elevated in manic patients.

The intracellular choline concentration in erythrocytes of manic patients who never had lithium therapy was 3 times the value for normal human subjects. Lithium therapy increased this value to 11 times normal, and the increase began within the first 2 days of lithium therapy. Plasma choline concentration was normal in untreated manic patients and did not change during lithium therapy.

Dystonic reactions following neuroleptics: time course and proposed mechanisms.

The occurrence of acute dystonic reactions was studied relative to drug pharmacokinetic parameters following a single dose of the phenothiazine, butaperazine. Dystonias occurred more than one half-life from peak butaperazine levels, 23 to 56 h after drug administration. The authors postulate that the appearance of dystonias on falling plasma concentrations may be due to disruption of dopaminergic-cholinergic balance caused by differential antidopaminergic and anticholinergic potencies of the drug.