Non-alcoholic fatty liver disease (NAFLD) has been associated with depression and inadequate response to antidepressants. While ketamine has demonstrated efficacy in treating depression, its impact on pre-existing liver injury and depression remains unclear. This study aimed to evaluate the effects of ketamine treatment in a murine model of depression and liver damage, considering age-related differences. Young and aged male C57BL/6N mice were submitted to chronic unpredictable mild stress (CUMS) and methionine–choline-deficient (MCD) diet to induce depressive-like behavior and NAFLD. Behavioral testing (sucrose preference test, open field test, novel object recognition test, Crawley’s sociability test) were used to assess ketamine’s (50 mg/kg) effect on behavior. Hepatic ultrasonography was utilized to evaluate liver status. The cortical and hippocampal NeuN+, GFAP+, and Iba1+ signals were quantified for each animal. Ketamine administration proved effective in relieving anhedonia and anxiety-like behavior, regardless of liver damage. Although ketamine treatment did not improve memory in animals with liver damage, it enhanced sociability, particularly in aged subjects. The acute administration of ketamine did not affect the severity of liver injury, but seems to affect astrogliosis and neuronal loss. Although animal models of depression only replicate certain clinical features of the condition, they remain valuable for evaluating the complex and varied effects of ketamine. By applying such models, we could demonstrate ketamine’s therapeutic versatility, and also indicate that responses to the treatment may differ across different age groups.

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.