Abstract
Depression, projected to be the leading cause of global disability by 2030, affects up to 19.62% of Pakistan's population. Treatment-resistant depression (TRD), characterized by poor response to at least two antidepressants, poses a major clinical challenge. Although interventions like ECT exist, their use is limited by systemic barriers. Esketamine, an NMDA receptor antagonist, offers a rapid-onset antidepressant effect and has shown higher remission rates compared to quetiapine in TRD trials. Despite promising evidence, esketamine is not currently available in Pakistan, and cost-related barriers hinder its adoption. Local studies suggest ketamine infusions are effective in TRD, including among ECT non-responders. Pakistan's centralized, specialist-dependent mental health system limits access to such novel treatments, particularly for rural and marginalized populations. Integrating esketamine requires addressing regulatory, infrastructural, and economic challenges while leveraging digital solutions and expanding community-based mental health services.