Design, Development and Evaluation of a Sequential Dual-Route Brain-Targeted Neurorestorative Platform for Psychoplastogen Therapeutics

Neuropsychiatric disorders, including major depressive disorder, anxiety, and substance use disorders, remain a major global health challenge due to delayed therapeutic onset, inadequate brain targeting, and high relapse rates associated with conventional pharmacotherapy. Increasing evidence suggests that these conditions are more closely associated with impaired neuroplasticity and synaptic dysfunction than with simple neurotransmitter imbalance. Psychoplastogens have emerged as a promising class of agents capable of rapidly inducing neural plasticity through glutamatergic modulation and activation of brain-derived neurotrophic factor (BDNF) and mechanistic target of rapamycin (mTOR) pathways. However, their effects are often transient, necessitating strategies that ensure sustained therapeutic outcomes. The present study proposes a dual-route brain-targeted drug delivery framework comprising an induction phase followed by a sequential maintenance (SIM) strategy, with exploratory consideration of microneedle-assisted transdermal delivery as a potential auxiliary approach. The induction phase employs intranasal administration for rapid nose-to-brain delivery, enabling immediate modulation of synaptic activity. The maintenance phase involves a depot-based system, utilizing biodegradable polymer-based depot system e.g., poly (lactic-co-glycolic acid) (PLGA), to provide sustained drug release and stabilization of neuroplastic changes. This integrated approach is based on temporal pharmacokinetic–pharmacodynamic alignment, combining rapid onset with prolonged therapeutic maintenance. The proposed system provides a rational and translationally relevant strategy for long-term outcomes in neuropsychiatric disorders.