BDNF, NEUROPLASTICIDADE E PSICODÉLICOS: UMA NOVA FRONTEIRA NO TRATAMENTO DA DEPRESSÃO RESISTENTE

Abstract

Depression is a complex and systemic mental disorder, associated with neuroendocrine, immunological, and brain connectivity alterations. The indiscriminate use of antidepressants, worsened by the COVID-19 pandemic (coronavirus disease 2019), represents a global public health issue, with self-medication rates ranging from 12.1% to 92.8% across countries. Traditional antidepressants, selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and tricyclics, present limitations: therapeutic latency of 2-6 weeks, non-response rates of approximately 50% in first-line treatment, and adverse effects compromising adherence. This narrative review investigated faster-acting therapeutic strategies, focusing on BDNF modulation through physical exercise and psychedelics (psilocybin). The search was conducted in PubMed, SciELO, Google Scholar, and CAPES Portal. Results showed that regular physical exercise modulates BDNF with acute (peak at 30 minutes) and chronic (≥12 weeks) effects. Psilocybin activates the 5-HT2A-BDNF-TrkB-mTORC1 axis, promoting neuroplasticity, with remission rates superior to escitalopram (57% vs. 28%). However, methodological challenges persist, including blinding issues, limited effect durability (sustained response of 20.3% at 12 weeks), and acute cognitive side effects (Hedges' g = 1.13). It is concluded that BDNF modulation represents a transformative pathway, with exercise and psychedelics as promising strategies, although their clinical implementation requires standardized protocols, controlled settings, and adequate psychotherapeutic support.