Unraveling Mechanism Behind Treatment-Resistant Depression

Philadelphia, November 2, 2023 – Major depressive disorder (MDD) is a widespread mental illness that is disabling for many. It has long been known that MDD has both genetic and environmental influences. In a new study in Biological Psychiatry, published by Elsevier, researchers identify a gene that interacts with stress to mediate aspects of treatment-resistant MDD in an animal model.

Jing Zhang, PhD, at Fujian Medical University and senior author of the study, said: “Emerging evidence suggests that MDD is a consequence of the collaboration between genetic risks and environmental factors, so it is critical to investigate how stress exposure and risk genes 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 aggressive 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 behavior by reducing the expression of BDNF and PSD95 by dephosphorylating two protein kinases, CaMKIIα and ERK, under stress exposure.

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

MDD is an extremely heterogeneous condition. Differences in the types of depression people experience influence how they respond to treatment. A large subgroup of people with depression do not respond to standard antidepressants and have ‘treatment-resistant’ symptoms of depression. These patients often respond to various medications, such as ketamine or esketamine, or to electroconvulsive therapy. Notably, esketamine significantly alleviated LHPP-induced depression-like behavior, while the traditional drug fluoxetine did not, suggesting that this mechanism may underlie some forms of treatment-resistant depression.

John Krystal, MD, editor of Biological Psychiatry, said of the work: “We have a limited understanding of the neurobiology of treatment-resistant forms of depression. This study identifies a risk mechanism for depression for stress-related behavior that does not meet a standard norm.” antidepressants, but respond well to ketamine. This may indicate that the risk mechanisms associated with the LHPP gene shed light on the poorly understood biology of treatment-resistant forms of depression.”

Dr. Zhang added, “Together, our findings identify LHPP as a key player causing stress-induced depression, implying that LHPP may become an effective strategy for MDD therapies in the future.”