Esketamine has rapid-onset antidepressant effects and may reduce postpartum depression in parturients with prenatal depressive symptoms. However, its adverse neuropsychiatric symptoms limits clinical application. Dexmedetomidine can alleviate these adverse symptoms and has independent antidepressant effect. This randomized, double-blind, placebo-controlled trial is designed to evaluate whether intranasal esketamine combined with dexmedetomidine can reduce the prevalence of postpartum depression in women with prenatal depressive symptoms.

Perinatal depression is a common mental disorder in women during the perinatal period. Many studies have shown that existence of prenatal depressive symptoms is an important risk factor of postpartum depression. Early identification of pregnant women with symptoms of prenatal depression, and providing appropriate interventions may play important roles in reducing the incidence of postpartum depression.

Ketamine is an NMDA-receptor antagonist. Esketamine, the S-enantiomer of ketamine, has a higher affinity for the NMDA receptor and is approximately twice as potent as ketamine in anesthesia and analgesia. Recent studies have demonstrated that ketamine and esketamine have marked rapid-acting antidepressant effects, but often accompanied by neuropsychiatric adverse effects, including dizziness, hallucinations, nightmares, and dissociative symptoms. Intranasal esketamine is approved for treatment-resistant depression.

Dexmedetomidine, a highly selective α2-adrenergic receptor agonist, is commonly used as a perioperative adjuvant. Recently, its potential role in psychiatric disorders has drawn increasing attention, with evidence suggesting preventive and therapeutic effects on anxiety, depression, and post-traumatic stress disorder. Intranasal dexmedetomidine has been safely used in both adults and children, particularly for procedural sedation and preoperative administration.

Combined use of esketamine with dexmedetomidine has been shown to reduce the neuropsychiatric adverse effects associated with esketamine alone, while also exhibiting synergistic sedative and analgesic effects. The investigators suppose that, for pregnant women with prenatal depressive symptoms, intranasal administration of a low-dose esketamine-dexmedetomidine combination after childbirth may reduce the incidence of postpartum depression with fewer neuropsychiatric side effects.

This randomized controlled trial is designed to investigate the effect of esketamine-dexmedetomidine combination administered intranasally after childbirth on the incidence of postpartum depression among paturients with prenatal depressive symptoms.

Inclusion Criteria:

• Pregnant women aged ≥18 years who are preparing for childbirth;
• Positive prenatal depression screening, defined as a Patient Health Questionnaire-9 (PHQ-9) score ≥5.

Exclusion Criteria:

• History of schizophrenia or existence of communication barriers;
• Severe obstetric complications, including severe preeclampsia, placenta accreta, HELLP syndrome, placenta previa, placental abruption, or ASA physical status classification >III;
• Contraindications to ketamine/esketamine, including refractory hypertension, severe cardiovascular disease (NYHA class ≥III), or hyperthyroidism;
• Contraindications to dexmedetomidine, including severe bradycardia (heart rate <50 bpm), or second-degree or higher atrioventricular block;
• Unsuitable for intranasal administration due to nasal cavity diseases (e.g., rhinitis, nasal polyps, or nasal congestion of any cause);
• Refusal to participate in this study or concurrent participation in another clinical trial.