Treatment Strategies for Perinatal Depression Beyond Conventional Antidepressants: A Narrative Review

Objectives: Perinatal depression is prevalent and affects the physical and psychological well-being of both mothers and their offspring. Conventional antidepressants represent the most commonly used pharmacological treatments. However, concerns about safety during pregnancy and breastfeeding persist, alongside limitations such as delayed onset of action and suboptimal response rates. This review comprehensively examines biological treatment strategies for perinatal depression, with a focus on evidence for conventional antidepressants, novel neurosteroid-based therapies, emerging experimental treatments including oxytocin and perioperative esketamine, and neuromodulation methods. Mechanism: Conventional antidepressants modulate monoamine neurotransmission. Novel agents such as brexanolone, zuranolone, and esketamine act through neurosteroid modulation and N-methyl-D-aspartate (NMDA) receptor antagonism, producing rapid antidepressant effects. Oxytocin, a neuropeptide involved in social bonding and stress regulation, contributes to maternal mood regulation. Neuromodulation techniques, including repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS), target relevant brain circuits. Findings in Brief: Evidence indicates a slight increase in the risk of congenital malformations, particularly cardiovascular (CV) defects, and birth complications such as preterm birth or low birth weight associated with antidepressant use. However, absolute risks remain small and warrant cautious interpretation, as maternal depression itself is linked to adverse birth outcomes. Late pregnancy exposure to antidepressants may increase the risk of neonatal withdrawal symptoms or persistent pulmonary hypertension, but clinical guidelines do not recommend tapering treatment solely to prevent these outcomes. Brexanolone, zuranolone, and esketamine have emerged as rapid postpartum treatments, often used alongside standard antidepressants. Intranasal oxytocin and perioperative esketamine administered during cesarean section show promise, warranting further study. Neuromodulation techniques like rTMS and tDCS offer potential as adjuncts or alternatives. Conclusions: Biological treatments for perinatal depression are evolving rapidly. While conventional antidepressants remain the foundation of therapy, neurosteroids, esketamine, and oxytocin offer promising complementary options. Neuromodulation methods provide emerging alternatives. Ongoing research is essential to establish their safety and efficacy in perinatal populations and tailor personalized treatments that balance maternal and fetal-neonatal health.