Brain Drug Delivery for Major Depressive Disorder and Treatment-Resistant Depression: From Brain Exposure to Clinical Translation

The treatment of major depressive disorder (MDD) and treatment-resistant depression (TRD) remains challenging because of delayed treatment onset, tolerability concerns, and the need for long-term management. Intranasal administration, molecular optimization, nanocarriers, blood–brain barrier (BBB)-targeted transport, and controlled drug release offer different approaches to improving antidepressant delivery. However, increased drug concentrations in the brain do not necessarily lead to better pharmacological effects; their value depends on whether the drug reaches its site of action and engages the relevant target. This review discusses the mechanisms, brain exposure, pharmacodynamic evidence, and clinical translation of different delivery strategies. Particular attention is given to the interpretive limitations of pharmacokinetic metrics and to the differences in evidence linking carrier distribution, functional cargo delivery, and antidepressant efficacy. Current clinical evidence is concentrated mainly on drugs that have entered clinical use, such as esketamine, whereas most novel targeted carriers and engineered extracellular vesicles remain at the preclinical stage. Their development requires identification of the specific drug-development bottleneck that each delivery system is intended to address, followed by validation of the relationships among effective brain exposure, pharmacological activity, safety, and formulation quality. An evaluation framework matched to the delivery mechanism may help determine whether delivery advantages observed experimentally can translate into meaningful therapeutic benefits.