Lithium neurotoxicity at low therapeutic doses Hypotheses for causes and mechanism of action following a retrospective analysis of published case reports.

Lithium has been the pharmacologic treatment for the management of manic-depressive illness for many years. While the therapeutic efficacy of lithium is invaluable, it can cause a variety of neurotoxicities at normal therapeutic doses or concentrations. A systematic search through the Medline database was performed. 41 Cases of neurotoxic adverse effects of lithium at low therapeutic concentrations were observed (< 65 years, 14 males & 21 females/> 65 years, 6 females). Although a higher percentage of female subjects experienced lithium neurotoxicity, no statistically significant difference between the two groups was noted (Fisher's exact test, P = 0.07). The analysis of the data shows that among case reports of lithium neurotoxicity, drug interaction effect is an important factor. More than 50% (51.2%) of the patients received at least one neuroleptic medication with their lithium treatment, 22% received concomitantly an antidepressant, 22% an antiepileptic (carbamazepine) and 17% an anxiolytic. It is our hypothesis that these drug associations are an important contributing factor to lithium neurotoxicity. The high percentage of neurotoxicity which is associated with neuroleptics warrant caution in the daily clinical practice when these two classes of medications are combined. It is hypothesised that neuroleptics, in particular the phenothiazines, might increase lithium influx in red blood cells and that the enhanced levels of lithium in the tissue may possibly be responsible for the neurotoxic effects. Concomitant administration of medications such as neuroleptics with lithium require caution with regular clinical observations and drug plasma concentration monitoring.