The Era of Rapid-Acting Antidepressants: Clinical Insights Into Ketamine, Esketamine, and Scopolamine

Background: Treatment-resistant depression (TRD) represents a major clinical challenge, being associated with high morbidity, increased suicide risk, and substantial socioeconomic burden. The need for rapidly acting interventions has driven the development of rapid-acting antidepressants (RAADs), such as ketamine, esketamine, and scopolamine. This study aimed to systematically review the efficacy, safety, and clinical applicability of these agents in TRD.Methods: Systematic review conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines. Searches were performed in PubMed/MEDLINE, Embase, Cochrane Library, and Scopus, including randomized clinical trials (RCTs) published between January 2000 and September 2025. Randomized clinical trials involving adults with TRD were included. The scopolamine trials enrolled patients with depressive disorders and were not restricted to protocol-defined TRD. Risk of bias was assessed using the Cochrane RoB 2 tool. The screening and data extraction processes were independently performed by two reviewers, with disagreements resolved by consensus or consultation with a third reviewer.Results: Seven clinical trials were included (2 ketamine, 3 esketamine, 2 scopolamine). Intravenous ketamine (0.5 mg/kg over 40 minutes) demonstrated onset of effect at approximately 110 minutes, with response rates up to 70% at 24 hours, although with limited duration (1–2 weeks). Intranasal esketamine (56 mg or 84 mg twice weekly), combined with oral antidepressants such as escitalopram, sertraline, duloxetine, or venlafaxine extended release (XR), significantly reduced Montgomery–Åsberg Depression Rating Scale (MADRS) scores over four weeks and lowered relapse risk (hazard ratio [HR] = 0.49). Intravenous scopolamine (4 µg/kg) showed effects within 1–3 days but with less consistency in larger samples.Conclusion: RAADs provide rapid antidepressant responses in TRD. Evidence is more consistent for acute intravenous ketamine use and for maintenance treatment with intranasal esketamine. Intravenous ketamine demonstrated the fastest onset of action, whereas esketamine presented stronger evidence for long-term maintenance and relapse prevention. Scopolamine remains experimental.