Chemistry:Antiglucocorticoid
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:
- Cortisol synthesis inhibitors: These drugs, such as metyrapone, aminoglutethimide, and ketoconazole, work by blocking the production of cortisol in the adrenal glands.[6]
- 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]
- 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
References
- ↑ "The native anti-glucocorticoid paradigm". The Journal of Steroid Biochemistry and Molecular Biology 100 (1–3): 95–105. July 2006. doi:10.1016/j.jsbmb.2006.03.001. PMID 16713254.
- ↑ 2.0 2.1 2.2 2.3 2.4 "Pharmacological management of Cushing's syndrome: an update". Arquivos Brasileiros de Endocrinologia e Metabologia 51 (8): 1339–48. November 2007. doi:10.1590/s0004-27302007000800020. PMID 18209872.
- ↑ 3.0 3.1 3.2 3.3 "Antiglucocorticoid and related treatments for psychosis". The Cochrane Database of Systematic Reviews 2016 (1). January 2016. doi:10.1002/14651858.CD006995.pub2. PMID 26725721.
- ↑ 4.0 4.1 "Antiglucocorticoids in psychiatry". Advances in Psychiatric Treatment 15 (4): 242–249. 2009. doi:10.1192/apt.bp.105.001834.
- ↑ "The Role of Inflammatory Proteins in Anti-Glucocorticoid Therapy for Treatment-Resistant Depression". Journal of Clinical Medicine 10 (4): 784. February 2021. doi:10.3390/jcm10040784. PMID 33669254.
- ↑ 6.0 6.1 6.2 6.3 6.4 "Glucocorticoid inhibition in the treatment of depression: can we think outside the endocrine hypothalamus?". Depression and Anxiety 26 (7): 641–9. 2009. doi:10.1002/da.20546. PMID 19133699.
- ↑ 7.0 7.1 Institute of Medicine (US) Committee on Antiprogestins: Assessing the Science (1993). "Chapter 5: Antiglucocorticoid Effects of Antiprogestins.". Clinical Applications of Mifepristone (RU 486) and Other Antiprogestins: Assessing the Science and Recommending a Research Agenda.. Washington (DC): National Academies Press (US). https://www.ncbi.nlm.nih.gov/books/NBK236375/.
 |  |
