The role of sphingolipids in major depressive disorder and associated cognitive impairment: interactions with monoaminergic signaling, neuroinflammation, and neurogenesis

HOERTEL N, Mühle C, Müller CP, CHAIEB H, SCHEER V, FAYAD M, SÁNCHEZ-RICO M, LIMOSIN F, Kornhuber J (2026)

Publication Type: Journal article, Review article

Publication year: 2026

Journal

Molecular Psychiatry Springer Nature

DOI: 10.1038/s41380-026-03649-6

Abstract

Major depressive disorder (MDD) represents a leading cause of disability. Despite decades of research focused on monoaminergic dysregulation, the exact pathophysiological mechanisms underlying MDD remain incompletely understood. This gap in knowledge has contributed to suboptimal therapeutic outcomes, with approximately one-third of MDD patients showing resistance to conventional treatments. Recent advances in lipidomics support that sphingolipids—including ceramides, sphingomyelins, and their metabolites—could play important roles in depression pathophysiology. This review examines the role of sphingolipid dysregulation in MDD and associated cognitive impairment, with a particular focus on interactions with neurogenesis and apoptosis, monoaminergic signaling, neuroinflammation, mitochondrial dysfunction and oxidative stress, glutamatergic signaling, and synaptic plasticity. Several clinical studies demonstrate altered sphingolipid profiles in MDD patients, with elevated ceramide levels correlating with depression severity. Preclinical evidence supports potential causal relationships between sphingolipid alterations and depressive behaviors through effects on neurotransmission, neuroplasticity, neurogenesis, mitochondrial function, and inflammatory processes. Many established antidepressants influence sphingolipid metabolism through distinct mechanisms—acting directly as functional inhibitors of acid sphingomyelinase (ASM) or modulating this pathway indirectly. This mechanistic convergence positions sphingolipid dysregulation as a potential central mediating node across major pathophysiological pathways in MDD and as a common pathway through which key risk factors may converge, potentially explaining its biological heterogeneity. Sphingolipid metabolism also offers a potential mechanistic explanation for the frequently observed cognitive deficits in MDD. This review synthesizes current evidence regarding sphingolipid involvement in depression pathophysiology and outlines promising avenues for personalized medicine through biomarker development and sphingolipid-targeted therapeutics.

Authors with CRIS profile

Christiane Mühle Department of Psychiatry and Psychotherapy Peter Christian Müller Department of Psychiatry and Psychotherapy Johannes Kornhuber Lehrstuhl für Psychiatrie und Psychotherapie

Involved external institutions

Hôpital Corentin-Celton, Hospital Corentin-Celton, APHP FR France (FR) Université Sorbonne Paris Cité FR France (FR)

How to cite

APA:

HOERTEL, N., Mühle, C., Müller, C.P., CHAIEB, H., SCHEER, V., FAYAD, M.,... Kornhuber, J. (2026). The role of sphingolipids in major depressive disorder and associated cognitive impairment: interactions with monoaminergic signaling, neuroinflammation, and neurogenesis. Molecular Psychiatry. https://doi.org/10.1038/s41380-026-03649-6

MLA:

HOERTEL, Nicolas, et al. "The role of sphingolipids in major depressive disorder and associated cognitive impairment: interactions with monoaminergic signaling, neuroinflammation, and neurogenesis." Molecular Psychiatry (2026).

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