Treatment-Resistant Depression: Augmentation Strategies and Emerging Therapies

Defining Treatment-Resistant Depression

Treatment-resistant depression (TRD) is generally defined as failure to achieve adequate response after two or more adequate trials of antidepressant therapy. The STAR*D trial demonstrated that with each successive treatment step, remission rates decline from 37% (Step 1) to 13% (Step 4), underscoring the clinical challenge of TRD management.

Lithium Augmentation: The Classical Approach

Lithium augmentation of antidepressant therapy remains the best-studied augmentation strategy with the strongest evidence base. Target serum levels of 0.6-0.8 mEq/L provide optimal efficacy with acceptable tolerability. Meta-analyses show lithium augmentation achieves response in approximately 40-50% of TRD patients.

Atypical Antipsychotic Augmentation

Aripiprazole (2-10 mg), quetiapine (150-300 mg), and brexpiprazole (1-3 mg) have FDA approval for adjunctive treatment of MDD. The evidence is strongest for aripiprazole augmentation, with NNT of approximately 7-10 for response compared to antidepressant monotherapy.