Lithium is generally regarded as a first-line option for the long-term treatment (ie, maintenance treatment, prophylactic treatment) of bipolar disorders. However, there is a substantial amount of uncertainty regarding the most efficacious plasma concentration of this drug for this indication.

To allow clinical psychiatrists to practice evidence-based medicine when it comes to decide which lithium levels to target in the long-term treatment of their patients with bipolar disorders.

We will present the available evidence from randomized controlled trials (RCTs) explicitly addressing the issue of optimal lithium levels, show new data from post-hoc analyses of more recent approval-seeking RCTs including lithium as a comparator drug, discuss the methodological limitations and pitfalls inherent in all these studies and address open questions still waiting to be answered.

The available evidence suggests that lithium levels ≥0.6 mmol/L will be necessary for optimal protection against both manic/mixed and depressive episodes. For most patients an increase in lithium levels beyond 0.8 mmol/L will not be associated with superior efficacy against either manic/mixed or depressive episodes. In contrast, lithium levels between 0.4 - 0.6 mmol/L may be sufficient, at least for some patients, for optimal protection against pure depressive episodes.

Lithium levels between 0.6 - 0.8 mmol/L seem to be associated with optimal protection against both manic/mixed and depressive episodes in the long-term treatment of bipolar disorders.