Pharmacotherapeutic Options in Drug-Resistant Bipolar Depression: From Molecular Mechanisms to Rational Polypharmacotherapy.
Biomedicines May 23, 2026 Dominik Jucha, Michał Klimas, Dominika Wiśniewska et al.
About 25% of people with bipolar disorder experience drug-resistant depression, where standard treatments fail. This paper reviews augmentation strategies and polypharmacotherapy for treatment-resistant bipolar depression. Atypical antipsychotics show limited efficacy and high side effects. Ketamine produces the fastest and strongest antidepressant effect with low risk of switching to mania. Pramipexole shows long-term promise but carries high risk of mania and impulse control disorders. Celecoxib, as anti-inflammatory therapy, significantly improved response and remission rates compared to escitalopram alone. Memantine showed only early, short-term benefit. The authors conclude that rational polypharmacotherapy targeting glutamatergic and inflammatory pathways is most promising, with ketamine having the greatest clinical potential.