Antiglucocorticoid

Antiglucocorticoid
Drug class
Mifepristone, an antiglucocorticoid that is used in the treatment of Cushing's syndrome.
Class identifiers
Synonyms	Glucocorticoid antagonist; Cortisol antagonist; Anticorticosteroid
Use	Cushing's syndrome, others
Biological target	Glucocorticoid receptor
Chemical class	Steroids
Legal status
In Wikidata

Antiglucocorticoid drugs are a class of medications that act to reduce the effects of glucocorticoids, primarily cortisol, in the body. ^[1] They include direct glucocorticoid receptor antagonists such as mifepristone and synthesis inhibitors such as metyrapone, ketoconazole, and aminoglutethimide. They are used to treat Cushing's syndrome. ^[2]

These drugs have also been investigated for their potential therapeutic benefits in various psychiatric disorders, particularly depression and psychosis. ^{[3] [4]} The rationale behind using antiglucocorticoids in psychiatry stems from the observed dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis in many psychiatric conditions, which often manifests as elevated cortisol levels. ^{[4] [5]}

Types

There are several types of antiglucocorticoid drugs, including:

1. Cortisol synthesis inhibitors: These drugs, such as metyrapone, aminoglutethimide, and ketoconazole, work by blocking the production of cortisol in the adrenal glands. ^[6]
2. Glucocorticoid receptor antagonists: Mifepristone (RU-486) is the primary example of this class, which directly blocks the action of cortisol at its receptor sites. ^{[3] [6]}
3. Steroid hormones: Dehydroepiandrosterone (DHEA) has been studied for its potential antiglucocorticoid effects. ^[3]

Therapeutic applications

Cushing's syndrome

Antiglucocorticoid drugs are a treatment option for Cushing's syndrome, a condition characterized by excessive cortisol production. These medications are primarily used in two scenarios: as preoperative treatment to manage symptoms and reduce surgical risks, and as a long-term solution when surgery has failed or is not feasible. ^{[7] [2]} The main antiglucocorticoid agents employed in treating Cushing's syndrome include steroidogenesis inhibitors such as metyrapone and ketoconazole, which block cortisol production, and mifepristone (RU-486), which directly antagonizes the glucocorticoid receptor. ^[2] Metyrapone and ketoconazole are often preferred as first-line pharmacological treatments, either as monotherapy or in combination, due to their efficacy in controlling hypercortisolemia. ^[2] However, careful monitoring is essential during treatment, as these drugs can potentially cause side effects and, in some cases, lead to adrenal insufficiency. ^[7] While antiglucocorticoid therapy has shown promise in managing Cushing's syndrome, it is generally considered an adjunctive treatment to surgery, which remains the definitive cure for most cases of the disorder. ^[2]

Psychiatric disorders

The use of antiglucocorticoid drugs for psychiatric disorders has yielded mixed results. Some studies have shown promise in treating major depression, particularly in cases with psychotic features. ^[6] However, a Cochrane review of antiglucocorticoid treatments for psychosis found no significant differences in overall psychotic symptoms, positive symptoms, or negative symptoms when compared to placebo. ^[3]

The mechanism of action for antiglucocorticoid drugs in psychiatric disorders is not fully understood. One hypothesis suggests that these drugs may work by reducing glucocorticoid enhancement of corticotropin-releasing hormone (CRH) action in certain brain regions, such as the central nucleus of the amygdala. ^[6] Additionally, these drugs may affect glucocorticoid receptor regulation, neuroactive steroids, and classical monoamine systems. ^[6]

See also

• Corticosteroid
• Antimineralocorticoid

References

1. Muller C, Hennebert O, Morfin R (July 2006). "The native anti-glucocorticoid paradigm". The Journal of Steroid Biochemistry and Molecular Biology. 100 (1–3): 95–105. doi:10.1016/j.jsbmb.2006.03.001. PMID   16713254.
2. Dang CN, Trainer P (November 2007). "Pharmacological management of Cushing's syndrome: an update". Arquivos Brasileiros de Endocrinologia e Metabologia. 51 (8): 1339–48. doi: 10.1590/s0004-27302007000800020 . PMID   18209872.
3. Garner B, Phillips LJ, Bendall S, Hetrick SE (January 2016). "Antiglucocorticoid and related treatments for psychosis". The Cochrane Database of Systematic Reviews. 2016 (1) CD006995. doi:10.1002/14651858.CD006995.pub2. PMC   10337649 . PMID   26725721.
4. McIsaac SA, Westrin Å, Young AH (2009). "Antiglucocorticoids in psychiatry". Advances in Psychiatric Treatment. 15 (4): 242–249. doi:10.1192/apt.bp.105.001834.
5. Strawbridge R, Jamieson A, Hodsoll J, Ferrier IN, McAllister-Williams RH, Powell TR, et al. (February 2021). "The Role of Inflammatory Proteins in Anti-Glucocorticoid Therapy for Treatment-Resistant Depression". Journal of Clinical Medicine. 10 (4): 784. doi: 10.3390/jcm10040784 . PMC   7920038 . PMID   33669254.
6. Kling MA, Coleman VH, Schulkin J (2009). "Glucocorticoid inhibition in the treatment of depression: can we think outside the endocrine hypothalamus?". Depression and Anxiety. 26 (7): 641–9. doi:10.1002/da.20546. PMC   3640810 . PMID   19133699.
7. Institute of Medicine (US) Committee on Antiprogestins: Assessing the Science (1993). "Chapter 5: Antiglucocorticoid Effects of Antiprogestins.". In Donaldson MS, Dorflinger L, Brown SS, et al. (eds.). Clinical Applications of Mifepristone (RU 486) and Other Antiprogestins: Assessing the Science and Recommending a Research Agenda. Washington (DC): National Academies Press (US).