New Clues to the Mechanism Behind Treatment-Resistant Depression

Major depressive disorder (MDD) is a widespread mental health condition that for many is disabling. In a new study researchers identified a gene that interacted with stress to mediate aspects of treatment-resistant MDD in an animal model.

Jing Zhang, PhD said, “Emerging evidence suggests that MDD is a consequence of the co-work of genetic risks and environmental factors, so it is crucial to explore how stress exposure and risk genes co-contribute to the pathogenesis of MDD.”

To do that, the authors used a mouse model of stress-induced depression called chronic social defeat stress (CSDS) in which mice are exposed to aggressor mice daily for two weeks. They focused on a gene called LHPP, which interacts with other signaling molecules at neuronal synapses. Increased expression of LHPP in the stressed mice aggravated the depression-like behaviors by decreasing expression of BDNF and PSD95 by dephosphorylating two protein kinases, CaMKIIα and ERK, under stress exposure.

MDD is an extremely heterogeneous condition. Differences in the types of depression experienced by people influence the way they respond to treatment. A large subgroup of people with depression fail to respond to standard antidepressant medications and have “treatment-resistant” symptoms of depression. These patients often respond to different medications, such as ketamine or esketamine, or to electroconvulsive therapy. Notably, esketamine markedly alleviated LHPP-induced depression-like behaviors, whereas the traditional drug fluoxetine did not, suggesting that the mechanism might underlie some types of treatment-resistant depression.

John Krystal, MD, Editor of Biological Psychiatry, said of the work, “We have limited understanding of the neurobiology of treatment-resistant forms of depression. This study identifies a depression risk mechanism for stress-related behaviors that fail to respond to a standard antidepressant but respond well to ketamine. This may suggest that the risk mechanisms associated with the LHPP gene shed light on the poorly understood biology of treatment-resistant forms of depression.”


Lvping Zhuang, Weijie Gao, Yanbing Chen, Wenting Fang, Hsuan Lo, Xiaoman Dai, Jie Zhang, Wanjing Chen, Qinyong Ye, Xiaochun Chen, Jing Zhang. LHPP in glutamatergic neurons of the ventral hippocampus mediates depression-like behavior by dephosphorylating CaMKIIα and ERK. Biological Psychiatry, 2023; DOI: 10.1016/j.biopsych.2023.08.026

Elsevier. “New clues to the mechanism behind treatment-resistant depression.” ScienceDaily. ScienceDaily, 2 November 2023. <>.

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