Considering bipolar depression a diagnostic and therapeutic challenge, distinct from unipolar depression and associated with significant morbidity and mortality, we aim to systematically review guidelines, consensus meetings and treatment algorithms on the acute treatment of bipolar depression to critically underline the role of mood-stabilizers.

The MEDLINe/PubMed/Index Medicus, PsycINFO/PsycLIT, Excerpta Medica/EMBASE, databases were searched using “depression”, “bipolar”, “mood-stabilizers”, “manic-depressive” and “treatment guidelines” as key words since 2005 onward.

Among mood-stabilizers, the use of lamotrigine is overall recommended as first-line choice. Monotherapy is suggested on the basis of several positives clinical trials, however, pooled data analysis showed that lamotrigine was only modestly useful. Valproate monotherapy is suggested as first-line treatment option in the WFSBP and BAP guidelines, and in combination with lithium or antidepressants, but it is not mentioned among first-line choices neither in monotherapy nor as adjunctive treatment in two guidelines (ICG, NICE).

Lithium monotherapy is suggested in three of all guidelines (ICG, BAP, CANMAT and ISBD) as first-line treatment on the basis of positive evidence, but it is not recommended as first-choice by WFSBP and NICE guidelines. Its combination with lamotrigine, valproate and other agents is instead recommended as first choice treatment.

In summary, mood-stabilizers are considered a key point in the management of bipolar depression, preferably in combination. Despite algorithms evidence-based could be helpful to guide clinicians, they always need the case by case pharmacotherapeutic consideration.