Lithium blood levels are conventionally described as being therapeutic from 0.5 to 1.5 mmol/l. Within this range, there is wide agreement that higher doses are associated with increasing numbers of side-effects, but there is disagreement as to whether this is uniformly accompanied by a better therapeutic effect. Gelenberg et al.(33) reported that higher doses of lithium in the 0.8 to 1.0 mmol/l range averaging 0.83 mmol/l were 2.6 times as effective as doses achieving blood levels in the lower therapeutic range of 0.4 to 0.6, averaging 0.54 mmol/l. This increased efficacy (i.e. lower risk of relapse) was achieved at the cost of a greater frequency of side-effects. Three times as many patients given doses in the high range withdrew from the study due to side-effects. A series of other studies suggest that low to moderate doses of lithium may be just as effective as those in the higher range.(3,35)
There is a considerable time lag before lithium reaches steady state levels and some attempts at lithium loading with large doses from the outset have not been successful. A certain amount of time is needed for lithium to gain access into the central nervous system compartment(36) and steady state levels are not typically achieved until five half-lives or approximately 6 days. With the advent of magnetic resonance spectroscopy, it has been found that lithium levels in the brain are half those in serum(3 38) and, based on one small study, may be better correlated with the degree of clinical response than serum levels. (39)
While lithium has traditionally been administered in two, three, or four times daily dosing regimens in attempts to achieve the most consistent and stable blood levels possible, several findings have led to changes in this pattern of dosing. Extended-release preparations are now available and suitable for twice-daily dosing. Even with the original preparation of lithium carbonate, many clinicians and investigators have administered lithium in single night-time doses in order to achieve the highest blood levels and potential side-effects during sleep and utilize the much lower trough levels at a time when the kidney, for example, can be relatively spared from continuously high lithium levels. Some investigators feel that this might be associated with lower long-term renal side-effects and preliminary data suggest that this paradigm may not be associated with any loss of clinical efficacy.
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