Intranasal Esketamine-dexmedetomidine Combination and Postpartum Depression

Official title

Impact of Intranasal Esketamine-dexmedetomidine Combination on Postpartum Depression in Parturients With Prenatal Depressive Symptoms: a Randomized, Double-blind, and Placebo-controlled Trial

Overview

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.

Detailed description

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.

Interventions

• Drug Esketamine-dexmedetomidine combination
  The dosage will be calculated based on body weight (approximately 0.4 μg/kg of dexmedetomidine and 0.2 mg/kg of esketamine). The mixture of study drugs will be administered via a nasal spray device, alternating between the two nostrils every 5 minutes, until the target dose is reached. The combination will be administered twice after childbirth with an interval of 12 hours (2 sessions in total).
• Drug Placebo
  The dosage (volume) will be calculated based on body weight in the same way as that in the intervention group. The placebo (normal saline) will be administered via a nasal spray device, alternating between the two nostrils every 5 minutes, until the target dose is reached. The placebo will be administered twice after childbirth with an interval of 12 hours (2 sessions in total).

Primary outcome measures

• Prevalence of depressive symptoms at 42 days postpartum [Time frame: At 42 days postpartum]

Secondary outcome measures (3)

• Prevalence of depressive symptoms at 7 days postpartum [Time frame: At 7 days postpartum]
• Treatment response rates at 7 and 42 days postpartum [Time frame: At 7 and 42 days postpartum]
• Prevalence of major depressive episode at 42 days postpartum [Time frame: At 42 days postpartum]

Eligibility criteria

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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Quadruple blind

Primary purpose

Treatment

Study locations

China · 1 center

• Peking University First Hospital — Beijing

Publications

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• Chernik DA, Gillings D, Laine H, Hendler J, Silver JM, Davidson AB, Schwam EM, Siegel JL. Validity and reliability of the Observer's Assessment of Alertness/Sedation Scale: study with intravenous midazolam. J Clin Psychopharmacol. 1990 Aug;10(4):244-51. PMID 2286697
• Huge V, Lauchart M, Magerl W, Schelling G, Beyer A, Thieme D, Azad SC. Effects of low-dose intranasal (S)-ketamine in patients with neuropathic pain. Eur J Pain. 2010 Apr;14(4):387-94. doi: 10.1016/j.ejpain.2009.08.002. Epub 2009 Sep 3. PMID 19733106
• Lu X, Tang L, Lan H, Li C, Lin H. A Comparison of Intranasal Dexmedetomidine, Esketamine or a Dexmedetomidine-Esketamine Combination for Induction of Anaesthesia in Children: A Randomized Controlled Double-Blind Trial. Front Pharmacol. 2022 Jan 27;12:808930. doi: 10.3389/fphar.2021.808930. eCollection 2021. PMID 35185548
• Li HP, Liu KP, Yao L. Dexmedetomidine in combination with ketamine for pediatric procedural sedation or premedication: A meta-analysis. Am J Emerg Med. 2021 Dec;50:442-448. doi: 10.1016/j.ajem.2021.08.073. Epub 2021 Aug 31. PMID 34492589
• Uusalo P, Seppanen SM, Jarvisalo MJ. Feasibility of Intranasal Dexmedetomidine in Treatment of Postoperative Restlessness, Agitation, and Pain in Geriatric Orthopedic Patients. Drugs Aging. 2021 May;38(5):441-450. doi: 10.1007/s40266-021-00846-6. Epub 2021 Mar 16. PMID 33728561
• Li A, Yuen VM, Goulay-Dufay S, Sheng Y, Standing JF, Kwok PCL, Leung MKM, Leung AS, Wong ICK, Irwin MG. Pharmacokinetic and pharmacodynamic study of intranasal and intravenous dexmedetomidine. Br J Anaesth. 2018 May;120(5):960-968. doi: 10.1016/j.bja.2017.11.100. Epub 2018 Feb 2. PMID 29661413

Identifiers

NCT: NCT07639099 · 2026-0287

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗