Antidepressants in Bipolar Depression: From Neurotransmitter Mechanisms to Clinical Challenges.

Bipolar disorder (BD) is characterized by the occurrence of manic/hypomanic and depressive episodes, with the latter having a significant impact on morbidity, mortality and overall quality of life. Current guidelines for bipolar depression provide limited treatment options, with only a few approved therapies. Despite these limitations, approximately 50-60% of individuals diagnosed with BD are prescribed antidepressants. However, the use of these medications remains controversial due to risks of manic induction, rapid cycling, and symptom destabilization. This review explores the neurotransmitter mechanisms underpinning the phases of BD, focusing on monoamines and assessing the efficacy and safety of different antidepressant medications in the treatment of bipolar depression. Norepinephrine and dopamine have been identified as neurotransmitters associated with both depressive and manic poles, with a proposed deficit in depression and an increase in mania. The evidence indicates that serotonin is deficient during depressive phases, yet its imbalance also manifests in mania. Selective serotonin reuptake inhibitors (SSRIs), which primarily increase serotonin levels, are generally safer than tricyclic antidepressants (TCAs) and show promising-though not definitive-results, especially when combined with mood stabilizers. Other newer-generation antidepressants may also have potential for the treatment of bipolar depression. The heterogeneity of mood disorders poses a significant challenge in the diagnosis of BD, which is often ambiguous and complex. The natural mood fluctuations associated with BD, in conjunction with the frequent comorbidities such as anxiety, render the treatment of this condition particularly challenging, particularly in the context of antidepressant therapy. While clinical trials are conducted with the utmost rigor, they frequently fail to account for the intricacies of the real-world context due to the strict inclusion criteria. The identification of predictors of effective antidepressant use, such as symptom severity and comorbid conditions, has the potential to enhance treatment outcomes. Future research should aim to identify individualized predictors and deepen understanding of mood disorder spectra to optimize antidepressant use in bipolar depression.