Novel approaches in depression treatment: from rapid-acting antidepressants to personalized interventions.

Major depressive disorder and treatment-resistant depression affect many people, and over half of patients do not respond adequately to first-line antidepressants. This review examines promising rapid-acting treatments, including psychedelic compounds like psilocybin, which is in late-stage trials, and neuroplastogen compounds. It also discusses repetitive transcranial magnetic stimulation, including the SAINT protocol, which has shown rapid antidepressant effects and is FDA-cleared for treatment-resistant depression. The ALTO-300 trial is evaluating an adjunctive treatment guided by an EEG biomarker, and a Phase 2 study reports outcomes varying by genotype, suggesting potential for genetically personalized interventions. Challenges include unblinding in psychedelic trials, scalability of neuromodulation, and need for validated biomarkers.

Study at a glance

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.