Novel approaches in depression treatment: from rapid-acting antidepressants to personalized interventions.
Clotilde Guidetti, Maurizio Fava, George I. Papakostas
Molecular Psychiatry June 25, 2026 DOI: 10.1038/s41380-026-03722-0 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Review Peer reviewed |
|---|---|
| Population | Patients with MDD and TRD |
| Interventions | Psilocybin repetitive transcranial magnetic stimulation Stanford Accelerated Intelligent Neuromodulation Therapy |
| Topics | Depression |
| Key findings | Psilocybin has advanced to late-stage trials, and the SAINT protocol is FDA-cleared for treatment-resistant depression, while ongoing research explores EEG biomarker-guided and genetically guided personalized treatments. |
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.
Comparable studies
Other narrative reviews on depression, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Synaptic Dysfunction in Depression: Potential Therapeutic Targets | 2012 | Review | |
| Mindfulness-Based Cognitive Therapy for Depression: A New Approach to Preventing Relapse | 2003 | Review | |
| Synthesizing the Evidence for Ketamine and Esketamine in Treatment-Resistant Depression: An International Expert Opinion on the Available Evidence and Implementation Adults with treatment-resistant depression | 2021 | Review | |
| Classic psychedelics: An integrative review of epidemiology, therapeutics, mystical experience, and brain network function. General population | 2019 | Integrative review | |
| Sudarshan Kriya Yogic Breathing in the Treatment of Stress, Anxiety, and Depression: Part II—Clinical Applications and Guidelines | 2005 | Review |
Citations in the library
Cites 67
- Psilocybin with psychological support for treatment-resistant depression: an open-label feasibility study. The Lancet Psychiatry May 17, 2016
- Trial of Psilocybin versus Escitalopram for Depression New England Journal of Medicine April 14, 2021
- REBUS and the Anarchic Brain: Toward a Unified Model of the Brain Action of Psychedelics Pharmacological Reviews June 20, 2019
- Psychedelics Promote Structural and Functional Neural Plasticity Cell Reports June 1, 2018
- Single-Dose Psilocybin for a Treatment-Resistant Episode of Major Depression. New England Journal of Medicine November 3, 2022
and 62 more in the library