HPA Axis Modulation in the Treatment of Mood Disorders

Ozbolt, Lauren B.; Nemeroff, Charles B.

doi:10.5772/51600

Cited by 2 publications

(3 citation statements)

References 104 publications

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“…Substituting this lower limit of 𝑥 2,𝑠𝑡 in equation (20) for adrenal growth, we obtain a positive net growth rate which means uncontrollable growth of the adrenal. Limiting adrenal growth by a carrying capacity, 𝐾 𝐴 , stabilizes the system.…”

Section: Pituitary Adenoma (Cushing's Disease)mentioning

confidence: 99%

“…It thus came as a disappointment when HPA medications useful in Cushing’s syndrome failed in clinical trials for MDD and BD (see Table 1) 20 . These drugs include cortisol- and ACTH-synthesis inhibitors and glucocorticoid receptor (GR) antagonists.…”

Section: Introductionmentioning

confidence: 99%

“…Interestingly, Cushing's tumors and corticosteroids frequently cause mood episodes [12][13][14][15][16] . This causal effect of elevated chronic cortisol on mood, as well as the strong association of stress and MDD, has raised the hope that cortisol-lowering drugs could improve mood disorder symptoms in MDD and BD [17][18][19] It thus came as a disappointment when HPA medications useful in Cushing's syndrome failed in clinical trials for MDD and BD (see Table 1) 20 . These drugs include cortisol-and ACTH-synthesis inhibitors and glucocorticoid receptor (GR) antagonists.…”

Section: Introductionmentioning

confidence: 99%

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Hormone circuit analysis explains why most HPA drugs fail for mood disorders and predicts the few that work

Milo,

Halber,

Raz

et al. 2024

Preprint

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Elevated cortisol causes morbidity in chronic stress and mood disorders, including metabolic and cardiovascular diseases. There is therefore interest in developing drugs that lower cortisol by targeting its endocrine pathway, the hypothalamic-pituitary-adrenal (HPA) axis. Several promising HPA-modulating drugs have, however, failed to lower long-term cortisol in mood disorders such as major depressive disorder despite their effectiveness in situations where high cortisol is caused by a tumor (Cushing’s syndrome). Why these drugs failed is not well understood. Here we use a mathematical model of the HPA axis to show that the pituitary and the adrenal glands compensate for the effect of drugs by adjusting their functional mass, a feedback compensation that is absent in Cushing tumors. To find potential drug targets, we carried out a systematicin silicoanalysis of points of intervention in the HPA axis. We find that only two interventions that target corticotropin-releasing hormone (CRH) can lower long-term cortisol. Other drug targets either fail to lower cortisol due to gland-mass compensation or lower cortisol but harm other aspects of the HPA axis. Thus, we identify potential drug targets, including CRH-neutralizing antibodies and CRH-synthesis inhibitors, for lowering long-term cortisol in mood disorders and in those suffering from chronic stress. More generally, this study indicates that understanding the slow compensatory mechanisms in endocrine axes can be crucial in order to prioritize drug targets.

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Section: Pituitary Adenoma (Cushing's Disease)mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Hormone circuit analysis explains why most HPA drugs fail for mood disorders and predicts the few that work

Milo,

Halber,

Raz

et al. 2024

Preprint

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The Preeminence of Early Life Trauma as a Risk Factor for Worsened Long-Term Health Outcomes in Women

Westfall

Nemeroff

2015

Curr Psychiatry Rep

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Early life trauma (ELT) comprises an array of disturbingly common distressing experiences between conception and the beginning of adulthood with numerous and significant potential long-term, even transgenerational, health consequences of great public health concern, including depression, cardiovascular disease, and other psychiatric and medical disorders, and neurobiological, psychological, and behavioral effects which are sufficiently robust to confound many types of biomedical research. The impact of ELT on a woman's health trajectory appears to vary with the specific characteristics of the ELT (e.g., type, number of different types, severity, and timing), the individual (e.g., age, genetics, epigenetics, personality, and cognitive factors), and the individual's environment (e.g., level of social support and ongoing stressors) and to be mediated to a significant extent by persistent changes in a number of biological systems, dysregulation of those governing the stress response chief among them. Growing knowledge of the risk factors and pathophysiological mechanisms by which ELT confers diathesis to various poor health outcomes and the unique treatment-response profiles of women with ELT will lead to much needed improvements in prevention, diagnostic, and therapeutic efforts, including more effective psychotherapy and pharmacotherapy approaches, hopefully making strides toward improvements in the lives of women everywhere and ending countless cycles of intergenerational trauma-associated pathology. This article attempts to broadly summarize the current state of knowledge about the long-term sequelae of ELT for women's health.

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HPA Axis Modulation in the Treatment of Mood Disorders

Cited by 2 publications

References 104 publications

Hormone circuit analysis explains why most HPA drugs fail for mood disorders and predicts the few that work

Hormone circuit analysis explains why most HPA drugs fail for mood disorders and predicts the few that work

The Preeminence of Early Life Trauma as a Risk Factor for Worsened Long-Term Health Outcomes in Women

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