Mood Stabilizers Are the First Line of Treatment for Bipolar Disorder

South Med J. 2026 May 4;119(5):274-278. doi: 10.14423/SMJ.0000000000001959.

ABSTRACT

Although lithium and other mood stabilizers remain the preferred agents for bipolar disorder, their clinical use has been declining steadily while antipsychotic and antidepressant use has been increasing. We performed an integrative review of efficacy, mechanisms of disease, and drug effects. The most reproduced biologic abnormality during the ill phases of bipolar disorder is elevated intracellular sodium. This has been proposed to directly lead to the symptoms of the disease. Lithium and mood stabilizers directly reduce or normalize intracellular sodium concentrations. Dopamine D2 receptor blockade by antipsychotic agents indirectly increases sodium pump activity, thereby also reducing intracellular sodium. Antidepressants increase intracellular sodium, which is believed to contribute to the destabilization of the illness. Lithium and mood-stabilizing anticonvulsant drugs inhibit sodium entry in an activity-dependent fashion that may directly normalize documented biologic abnormalities in manic or depressed bipolar patients. This action makes them the preferred first-line pharmacologic agents. Antipsychotic medication indirectly lower intracellular sodium and would be reasonable adjunctive or second-line agents. Serotoninergic antidepressants increase intracellular sodium, which may explain why they destabilize the illness and should be avoided or used as third-line agents.

PMID:42067390 | DOI:10.14423/SMJ.0000000000001959