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. 2026 Oct 17;20:646618. doi: 10.2147/DDDT.S646618

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© 2026 Zhong et al.

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Diagram of analgesic, mood-related and sleep-related pathways with sites, pathways, outcomes and evidence. A diagram shows three pathways: A. Analgesic, B. Mood-related and C. Sleep-related. A. Analgesic pathway: Located in the spinal dorsal horn, involving Adelta/C nociceptors to the brain. It suggests NMDAR antagonism, central sensitization and wind-up, leading to reduced early pain. Opioid effects are inconsistent. Evidence supports short-term analgesia more than opioid sparing. B. Mood-related pathway: Involves prefrontal cortex-hippocampal circuits with glutamatergic disinhibition, AMPAR activation and BDNF-mTOR synaptic plasticity. It may reduce early postpartum depressive symptoms. Evidence is mixed, with direct obstetric trials but varied results. C. Sleep-related pathway: Involves sleep-wake networks, hypothalamus, brainstem, slow-wave and REM. It may modulate slow-wave and REM activity, improving subjective sleep outcomes. Evidence is mostly indirect, with objective sleep data mainly non-obstetric. — Proposed pathways linking peripartum esketamine with analgesic, mood-related, and sleep-related outcomes. (A) illustrates the proposed analgesic pathway, including nociceptive processing in the spinal dorsal horn, NMDAR antagonism, and attenuation of central sensitization. Direct obstetric evidence is most consistent for short-term analgesic outcomes, whereas opioid-sparing effects are less consistent. (B) illustrates the proposed mood-related pathway, including prefrontal–hippocampal circuits, glutamatergic signaling, AMPAR activation, and BDNF–mTOR-related synaptic plasticity. Clinical evidence for early postpartum depressive symptoms remains heterogeneous and derives predominantly from screening-based outcomes. (C) illustrates the proposed sleep-related pathway, including sleep–wake networks and possible modulation of slow-wave and REM-related activity. Postpartum sleep-related evidence remains predominantly subjective, while objective sleep-architecture evidence is mainly indirect and non-obstetric. Solid lines indicate relationships supported predominantly by direct obstetric clinical evidence, dashed lines indicate mixed direct and indirect evidence, and dotted lines indicate predominantly indirect evidence. These proposed pathways are conceptual and do not establish causality.

Abbreviations: AMPAR, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; BDNF, brain-derived neurotrophic factor; mTOR, mammalian target of rapamycin; NMDAR, N-methyl-D-aspartate receptor; REM, rapid eye movement.