Toward Long-Acting Injectable Antidepressants: Drug-Delivery Strategies, Clinical Considerations, and Regulatory Barriers

Long-acting injectable (LAI) systems may offer an alternative approach to antidepressant treatment by reducing reliance on daily oral medication, supporting adherence, limiting pharmacokinetic fluctuations, and maintaining therapeutic drug exposure over extended periods. These potential advantages may be particularly relevant for patients with recurrent depression or difficulty sustaining regular oral treatment. However, converting conventional antidepressants into clinically useful LAIs remains challenging because many drugs require substantial maintenance doses, have formulation-limiting physicochemical properties, and may require dose adjustment or prompt discontinuation in response to adverse effects. This review evaluates the feasibility of established and emerging depot technologies, including polymeric microspheres, in situ-forming depots, lipid- and oil-based systems, hydrogels, and hybrid or stimulus-responsive platforms, for sustained antidepressant delivery. It compares these approaches according to drug-loading capacity, release mechanisms, achievable dosing interval, injection-volume constraints, manufacturing scalability, sterilization, product robustness, safety, local tissue tolerability, and regulatory maturity. Major translational barriers include the high total drug mass required for many antidepressants, acceptable injection-volume limits, solvent and excipient safety, injection-site reactions, limited reversibility after administration, pharmacokinetic drug-interaction risk, difficulty developing predictive in vitro–in vivo correlations and demanding regulatory expectations for complex injectable products. The review also considers opportunities for coordinated long-acting combination therapy, personalized patient selection, digital adherence monitoring, and emerging biomaterials. Overall, successful LAI antidepressant development will require careful matching of the drug molecules, delivery platform, pharmacokinetic target, and intended patient population. Early products are most likely to rely on established depot technologies and prior confirmation of oral efficacy and tolerability before long-term administration.