Treatment-resistant peripartum depression (TRPD) is a significant public health concern due to the dual imperative of maternal symptom relief and fetal/neonatal safety with complex therapeutic challenges, particularly among expecting mothers worldwide. This comprehensive review focused on current pharmacological and non-pharmacological interventions for treatment-resistant depression (TRD)/peripartum depression (PPD), highlighting their mechanisms, efficacy, safety profiles, and practical considerations. The search strategy is based on PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analysis), using a systematic search of PubMed, Cochrane Library, and EMBASE for English-language articles published between 2000 and 2024, with a combination of Medical Subject Headings (MeSH) and free-text terms for TRD/TRPD. After screening, the initial search yielded 142 articles; only 67 articles were qualified for eligibility and quality assessment. According to related research, pharmacological treatments such as SSRIs or brexanolone and zuranolone can be effective in addressing TRPD challenges, but they carry concerns regarding fetal and neonatal risk. In contrast, non-pharmacological interventions-such as cognitive behavioral therapy (CBT), repetitive transcranial magnetic stimulation (rTMS), and exercise-offer safe, evidence-based alternatives that are becoming increasingly accessible. Our findings imply that innovative therapeutics and integration of these interventions personalized to individual needs are the optimal clinical approach that may help in balancing maternal symptom control and perinatal safety. Also, expanded mental health infrastructure with enhanced research is essential for advancing TRPD care.

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