Major depressive disorder (MDD) is a prevalent mental health condition that can be highly debilitating for many individuals. It has long been recognized that MDD arises from a combination of genetic and environmental factors. In a recent study published in Biological Psychiatry by Elsevier, researchers have pinpointed a gene that interacts with stress to influence certain aspects of treatment-resistant MDD in an animal model.

Dr. Jing Zhang, PhD, from Fujian Medical University and the senior author of the study, stated, “Emerging evidence indicates that MDD results from the interplay of genetic predispositions and environmental elements, highlighting the importance of investigating how stress and risk genes jointly contribute to the development of MDD.”

To explore this, the authors employed a mouse model of stress-induced depression known as chronic social defeat stress (CSDS), where mice are exposed to aggressive mice on a daily basis for two weeks. They focused their attention on a gene called LHPP, which interacts with other signaling molecules at neuronal synapses. Elevated expression of LHPP in the stressed mice exacerbated depression-like behaviors by reducing the expression of BDNF and PSD95 through the dephosphorylation of two protein kinases, CaMKIIα and ERK, under conditions of stress.

Dr. Zhang pointed out, “Interestingly, LHPP mutations (E56K, S57L) in humans may enhance CaMKIIα/ERK-BDNF/PSD95 signaling, suggesting that carrying LHPP mutations might have an antidepressant effect in the population.”

MDD is an incredibly diverse condition. Variations in the types of depression experienced by individuals influence their response to treatment. A significant subset of individuals with depression do not respond to standard antidepressant medications and exhibit symptoms of depression that are “treatment-resistant.” These patients often show positive responses to alternative medications like ketamine or esketamine, or to electroconvulsive therapy. Notably, esketamine substantially alleviated depression-like behaviors induced by LHPP, whereas the traditional drug fluoxetine did not, indicating that this mechanism may underlie certain forms of treatment-resistant depression.

Dr. John Krystal, MD, Editor of Biological Psychiatry, commented on the study, stating, “Our understanding of the neurobiology underlying treatment-resistant forms of depression is limited. This study identifies a mechanism linked to depression risk in stress-related behaviors that do not respond to standard antidepressants but do respond well to ketamine. This suggests that the risk mechanisms associated with the LHPP gene shed light on the poorly understood biology of treatment-resistant forms of depression.”

Dr. Zhang concluded, “Taken together, our findings highlight LHPP as a crucial factor driving stress-induced depression, implying that targeting LHPP could be an effective approach in future therapeutic strategies for MDD.”


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