Sequential esketamine and dextromethorphan-bupropion in treatment-resistant depression with bipolar features: A case report

• Sequential esketamine then dextromethorphan-bupropion led to sustained remission • Esketamine provided rapid induction benefit in treatment-resistant depression • Dextromethorphan-bupropion maintained long-term stability without mania Treatment-resistant depression (TRD) remains a major clinical challenge, particularly in patients with bipolar spectrum features where standard antidepressants often fail. Novel glutamatergic and sigma-1 receptor–modulating agents such as intranasal esketamine and dextromethorphan-bupropion (Auvelity) offer promising alternatives. We report the case of a 43-year-old male with recurrent depression and bipolar II features who had failed eight antidepressant and mood-stabilizing trials over two decades. A four-week course of intranasal esketamine at Kings County Hospital Center produced marked improvement, with remission lasting approximately six months. After relapse, treatment with dextromethorphan-bupropion led to renewed and sustained recovery without mania or hypomania. This sequential response suggests esketamine may serve as an induction treatment, with dextromethorphan-bupropion providing a feasible maintenance option in TRD with bipolar features. The case highlights the importance of recognizing bipolarity in treatment-resistant presentations and demonstrates the potential of sequential glutamatergic and sigma-1 receptor–modulating therapies when long-term esketamine is impractical. Controlled studies are warranted to identify predictors of response, long-term safety, and optimal treatment sequencing.