Novel approaches in depression treatment: from rapid-acting antidepressants to personalized interventions.
Clotilde Guidetti, Maurizio Fava, George I Papakostas
Molecular psychiatry June 25, 2026 Peer reviewed DOI: 10.1038/s41380-026-03722-0 via PubMed
Summary
Rapid-acting treatments for major depressive disorder (MDD) and treatment-resistant depression (TRD) are critically needed, as over 50% of patients do not respond adequately to first-line antidepressants. This review discusses promising options like psilocybin, which is in late-stage trials, and repetitive transcranial magnetic stimulation (rTMS), particularly the Stanford Accelerated Intelligent Neuromodulation Therapy (SAINT) protocol, now FDA-cleared for TRD. The ALTO-300 trial is also evaluating a new adjunctive treatment based on EEG biomarkers.
Study at a glance
| Design | review |
|---|---|
| Key finding | Psilocybin and rTMS, especially the SAINT protocol, show promise as rapid-acting treatments for MDD and TRD. |
Abstract
Major depressive disorder (MDD) and treatment-resistant depression (TRD) are prevalent and debilitating conditions. Over 50% of patients have inadequate response to first-line serotonergic antidepressants and are left with suboptimal treatment options. Rapid-acting and individually tailored treatments for MDD remain major unmet needs. This review discusses promising rapid-acting treatments, including psychedelic and neuroplastogen compounds, currently under investigation for the treatment of MDD and TRD. Among these, psilocybin has advanced to late-stage trials. In addition, we examine the emerging role of repetitive transcranial magnetic stimulation (rTMS), including novel personalized interventions, such as the Stanford Accelerated Intelligent Neuromodulation Therapy (SAINT) protocol, which has demonstrated rapid antidepressant effects and is now FDA-cleared for TRD, positioning it closest to clinical translation. We also highlight the ongoing ALTO-300 trial, which is evaluating an adjunctive treatment for MDD in patients identified by an EEG biomarker-representing another promising step toward personalized treatment. Finally, we review the results of a Phase 2 study reporting outcomes that vary by a specific genotype sequence, underscoring the potential for genetically guided personalized interventions. Despite these advances, key limitations, including unblinding in psychedelic trials, scalability challenges of intensive neuromodulation protocols, and the need for validated biomarkers, pose ongoing challenges for real-world implementation.