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Gene & Protein in Disease Orexin in depression

failure stress causes a long-term decrease in pre–pro orexin Orexin possesses the ability to control hormone levels,
mRNA expression at the orexin gene promoter through eating habits, and sleep–wake cycles and may be closely
epigenetic modification, whereas calorie restriction involved in the pathophysiology of major depressive
improves orexin cell activation after social defeat. To disorder (MDD), a severe mood disorder potentially
summarize, orexin is crucial in regulating the decrease in influenced by abnormalities of neurotransmitters in
depression-like symptoms caused by calorie restriction. 65 orexin neurons. Studies have determined whether the
Decreased orexin function is a potential reason why OX1R and OX2R genes contribute to the onset of MDD.
people at a high risk of developing cardiovascular diseases A study comparing 87 healthy controls and 75 patients
are prone to depression. Although the exact cause of with MDD revealed that substantial differences were found
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depression in patients with cardiovascular diseases such in the genotype frequencies of the OX1R gene variants
as obstructive sleep apnea (OSA) and sudden infant death rs10914456 and rs2271933, whereas the Orx2 rs2653349
syndrome (SIDS) remains unknown, patients with OSA genotype showed no association with MDD development.
and SIDS experience recurrent episodes of respiratory The rs10914456 and rs2271933 loci of the OX1R gene may
arrest and/or insufficient breathing, causing hypoxia/ be related to the pathogenesis of depression. The OX1R
hypercapnia (H/H). 67,68 Those studies investigated the rs10914456 variant may affect the severity of depressive
responses of fluorescently identified rat orexin neurons in symptoms. 70
the LH to acute H/H to test whether and how these neurons According to preclinical research, a strong correlation
alter their activity and function during this challenge; the exists between orexin and stress-related diseases. In
results suggested that the inhibition of orexin neurons is addition, orexin is involved in regulating animal reward
related to the H/H-induced reduction of glutamatergic and motivation, inferring that a potential association
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neurotransmission within orexin neurons. exists between the orexin energy system and depression in
Overall, the orexin system has demonstrated remarkable human subjects. Numerous studies in adults have indicated
regulatory functions across different animal models of a negative correlation between MDD and orexin levels. 72,73
depression, suggesting that its control in depression is Nevertheless, these studies have primarily focused on
universal. Although there is a close relationship between adults, with limited research conducted on adolescents.
orexin and mood disorders, current research primarily Considering the distinctions between adult and adolescent
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depends on animal models, which to some extent limits depression, as well as the understanding that orexin
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translational research related to clinical practice. Moreover, receptor expression tends to decrease with age, the
most existing studies focus on the acute effects of orexin, association between MDD and orexin levels could differ
ignoring the relevance of long-term effects. Therefore, future among adolescents. Serum OXA levels were compared
studies should incorporate chronic models and further between adolescents with MDD and healthy controls using
investigate the role of the orexin system in different subtypes ANCOVA; in the MDD group, correlation analysis and
of depression to obtain findings with greater clinical relevance. linear regression were also used to analyze the correlation
between OXA levels and the childhood depression
4. Relationship between orexin and scale. After controlling for body mass index, sex, age,
depression in clinical research and anxiety levels, OXA levels in depressed individuals
were comparable to those of controls. Moreover, neither
Considering the progress of animal model studies in correlation nor regression analysis revealed an association
clarifying the regulatory role of the orexin system in between OXA and depressive symptoms, implying that
depression, the next logical step is to translate these OXA was not related to adolescent depression. 76
findings into clinical applications. Although clinical
research into the relationship between orexin and Childhood abuse results in neuroendocrine alterations,
depression is relatively recent, some studies have started which may be associated with an increased vulnerability to
investigating the correlation between orexin levels and psychiatric pathology, such as depression and anxiety. 77,78
depressive symptoms. The orexin system plays a crucial Reportedly, the relationship between childhood abuse and
role in regulating arousal, wakefulness, and appetite orexin levels in patients with depression and anxiety was
and is implicated in the pathophysiology of depression. investigated using the Childhood Trauma Questionnaire
Reportedly, the orexin system dysregulation contributes to (CTQ) to evaluate the history of childhood trauma in
the development of depressive symptoms, including sleep 27 women with depression or anxiety symptoms and
disturbances predominantly associated with depression. 27 healthy women controls. Serum levels of orexin and
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We review the existing clinical research to explore the role cortisol were measured in all participants. Results showed
of the orexin system in human depression. that orexin levels in patients’ serum positively correlated

Volume 4 Issue 2 (2025) 10 doi: 10.36922/gpd.4210