Hydrogel-Based Depot Systems in Psychiatric Pharmacotherapy: A Narrative Review Rethinking Long-Acting Drug Delivery

Poor adherence to pharmacotherapy remains a major challenge in the long-term management of severe psychiatric disorders. Although long-acting injectable (LAI) antipsychotics can provide effective and sustained drug exposure while supporting treatment continuity, their pharmaceutical and clinical characteristics vary considerably according to the active pharmaceutical ingredient and formulation technology. Specific formulations may be associated with limitations such as complex release kinetics, injection-site reactions, or the need for oral supplementation during treatment initiation. Hydrogel-based delivery systems have emerged as a versatile class of biomaterials that may address these limitations through their tunable physicochemical properties, high water content, biocompatibility, and capacity for controlled, sustained drug release. Their adaptable architecture further enables diverse drug-loading strategies and multiple routes of administration, expanding the design space for next-generation long-acting formulations. In this narrative review, we provide a comprehensive overview of hydrogel-based depot systems for psychiatric pharmacotherapy, focusing on hydrogel composition (natural, synthetic, and hybrid polymers), crosslinking mechanisms, stimuli-responsive and injectable formulations, drug loading and release strategies, and their translational potential. Current research has primarily focused on antipsychotic delivery, where hydrogel formulations of risperidone, paliperidone, aripiprazole, olanzapine, quetiapine and the investigational peptide PAOPA show possible sustained drug release and prolonged therapeutic activity in preclinical models. Compared with conventional depot technologies, hydrogel systems may offer greater formulation flexibility and the potential for more controlled pharmacokinetic profiles and prolonged drug exposure. These characteristics could ultimately support reduced dosing frequency and treatment continuity. We also discuss the key challenges limiting clinical translation, including optimization of release kinetics, scalable manufacturing, sterilization, long-term stability, and regulatory considerations. Collectively, current evidence supports the technological potential of hydrogel-based systems to provide tunable drug loading, depot formation, and sustained release. However, their development as clinically meaningful next-generation LAI therapies will require long-term in vivo evaluation, robust pharmacokinetic-pharmacodynamic characterization, injection-site safety assessment, reproducible and scalable manufacturing, and well-designed clinical trials.