Trazodone in neurology, a new life for an old molecule - an updated, comprehensive, systematic review of clinical trials

The triazolopyridine derivative trazodone is approved for the treatment of major depressive disorder (MDD) in adults; according to the available literature, this molecule, through a specific dose-dependent profile of action, was found to be a potential therapeutic option in some neurological conditions. This systematic review aimed to synthesise the available evidence on the use of trazodone in neurological patients. PubMed was searched for articles published from inception until March 2025. Article reference lists were screened, and relevant articles were retrieved for consultation. Clinical trials specifically investigating trazodone in neurological populations were included, following PRISMA guidelines for systematic reviews. Out of 69 records initially retrieved, 14 studies met the inclusion criteria, comprising 13 randomised controlled trials and 1 retrospective study, with a total of 608 patients. Most of the included studies focused on individuals with dementia, while others explored its use in different neurological disorders. Despite being an older antidepressant, trazodone remains widely prescribed. Beyond treating depression in neurological patients, it may may be useful in the treatment of some neurological aspects. However, current evidence remains limited. Further high-quality research is necessary to better define the therapeutic potential of trazodone in the management of neurological conditions. The antidepressant trazodone, which is approved for the treatment of major depressive disorder in adults, was found to be a valid therapeutic option in the treatment of some clinical aspects in various neurological conditions.In addition, current evidence suggests that trazodone, through activation of PPARγ (peroxisome proliferator-activated receptor gamma) receptors, may modulate several pathophysiological processes, that are relevant in neurodegenerative diseases, such as Alzheimer’s - and Parkinson’ s disease.Since the variability in therapeutic responses to trazodone may depend on factors such as stage of the neurological disease and specific pharmacokinetics, future studies on this molecule should include phenotypic and molecular characterisation of patients, as well as the use of biomarkers predictive of response. The antidepressant trazodone, which is approved for the treatment of major depressive disorder in adults, was found to be a valid therapeutic option in the treatment of some clinical aspects in various neurological conditions. In addition, current evidence suggests that trazodone, through activation of PPARγ (peroxisome proliferator-activated receptor gamma) receptors, may modulate several pathophysiological processes, that are relevant in neurodegenerative diseases, such as Alzheimer’s - and Parkinson’ s disease. Since the variability in therapeutic responses to trazodone may depend on factors such as stage of the neurological disease and specific pharmacokinetics, future studies on this molecule should include phenotypic and molecular characterisation of patients, as well as the use of biomarkers predictive of response.