Trilostane: Beyond Cushing's Syndrome.

Simple Summary: Drugs rarely are aimed at a single target. More frequently, drugs can affect the functioning of multiple systems as a consequence of the different levels of activity of the aimed target or because of the effects caused by drug interactions with the other possible targets. Trilostane is a veterinary drug used for very specific diseases, but the array of possible beneficial effects generated by trilostane could be useful for diseases different from those indicated for the use of this drug. Additionally, although abandoned as a drug to treat diseases in human patients, the use of trilostane in animals to address conditions still needing effective therapies could give trilostane appeal for a new appraisal in disorders common to humans and animals, such as epilepsy, anxiety, and depression. This review of the present evidence suggests that trilostane is a powerful tool to stimulate the production of hormones (steroids), making the brain more resilient to injuries and traumatic events, preventing more negative consequences caused by the triggered neuroinflammatory responses (a consequence common to seizures and, but not only, depression), which definitely could lead to more severe conditions. Trilostane is a drug able to block the synthesis of progesterone from pregnenolone, dependent on the enzyme 3β-hydroxysteroid dehydrogenase/Δ5−4 isomerase. As a consequence of this effect, it is used to treat endocrinological diseases such as Cushing's syndrome, especially in dogs. Because of the modulatory effects of trilostane on the hypothalamic–pituitary–adrenal axis, trilostane administration causes an increase in brain levels of neurosteroids with anticonvulsant properties, as in the case of allopregnanolone. Allopregnanolone is also of interest in curing depression, suggesting that trilostane might represent a tool to address neurological and psychiatric disorders. In this review, we investigated the historical development of this drug and its current use, mechanisms, and possible developments. By searching the literature from 1978 to 2025, we identified 101 papers describing studies with trilostane. Precisely, 55 were about dogs and trilostane, 3 were on cats, and 23 were with other animals. Some studies (15) were also designed with human patients. The main disease treatment with trilostane was hyperadrenocorticism. However, we also found two preclinical papers on trilostane's potential use in psychiatric diseases and three on trilostane's potential use in neurological disorders. Moreover, few clinical and preclinical studies suggested the involvement of neurosteroids modulated by trilostane in different neurological disorders, thus opening a possible new perspective for the use of this drug. [ABSTRACT FROM AUTHOR]