Targeting the brain: alternative administration routes and drug delivery systems for antidepressant therapy

INTRODUCTION: Although numerous antidepressants are clinically available, they are characterized by slow therapeutic onset, systemic effects, and limited brain exposure, which is restricted by the blood-brain barrier (BBB). AREAS COVERED: Alternative administration routes namely intranasal, ocular, and intratympanic delivery, are emerging as promising strategies for a direct drug targeting of the central nervous system. Data were obtained from PubMed, Web of Science, Scopus, and regulatory agencies, 2010-2025. Intranasal route enables rapid brain delivery through the olfactory and trigeminal pathways, bypassing the BBB and avoiding systemic degradation. Ocular delivery allows drugs to reach the retina and optic nerve, providing access to deeper brain structures, while intratympanic route facilitates drug passage into the inner ear and subsequently into the cerebrospinal fluid through its connection to the cochlear perilymph, circumventing the BBB. EXPERT OPINION: Innovative drug delivery systems have the potential to enhance drug stability, brain permeability, and enable sustained and targeted release. By integrating these technologies with novel administration routes, which allow direct brain delivery, it may be possible to enhance cerebral biodistribution, speed therapeutic onset, reduce systemic side effects. This is a crucial area of ongoing research, offering the potential for safer, more effective, and patient-centered treatments for depression.