Trazodone

Trazodone is a 5-hydroxytryptamine antagonist and reuptake inhibitor (SARI). Trazodone inhibits SERT, antagonizes 5-HT2A/5-HT2C, activates 5-HT1A, blocks α1-adrenergic receptors and H1-histamine receptors, and reduces neuroinflammation and proteostasis damage by regulating the PERK/UPR and sST2-related microglial pathways. Trazodone can be used for studies on major depressive disorder, insomnia, anxiety/post-traumatic stress-related sleep disorders, and Alzheimer's disease^[1-4].

In vitro, LS180V cells were treated with 10µM trazodone for 72 hours. Trazodone increased P-gp expression, enhanced P-gp-mediated efflux activity^[5]. Cardiomyocytes were treated with 3-10µM trazodone. Trazodone immediately decreased the maximum upstroke velocity of action potentials and prolonged action potential duration^[6]. LPS-induced BV-2 cells were treated with 0-2µM trazodone for 24 hours. Trazodone inhibited cell growth, decreased TNF-α, IL-6, IL-1β, and ROS levels^[7].

In vivo, C57BL/6J mice received a single oral dose of 10-60mg/kg trazodone. Trazodone dose-dependently increased non-rapid eye movement sleep and NREM delta power, and decreased rapid eye movement sleep and wakefulness^[8]. tg37^+/- prion disease mice received daily intraperitoneal injections of 40mg/kg trazodone for 6 days. Trazodone restored the synthesis rate of nascent proteins in hippocampal neurons and astrocytes, and restored the number of synapses and mitochondria and mitochondrial respiratory function^[9]. C57BL/6 mice received daily intraperitoneal injections of 36mg/kg trazodone for 21 days starting 24 hours after middle cerebral artery occlusion. Trazodone improved sensorimotor function, motor coordination, and emotional/exploratory behavior^[10].

References:
[1] de Meester A, Carbutti G, Gabriel L, et al. Fatal overdose with trazodone: case report and literature review. Acta Clin Belg. 2001 Jul-Aug;56(4):258-61.
[2] Wichniak A, Wierzbicka AE, Jarema M. Treatment of insomnia - effect of trazodone and hypnotics on sleep. Psychiatr Pol. 2021 Aug 31;55(4):743-755.
[3] Rawls WN. Trazodone (Desyrel, Mead-Johnson Pharmaceutical Division). Drug Intell Clin Pharm. 1982 Jan;16(1):7-13.
[4] Martinon-Torres G, Fioravanti M, Grimley EJ. Trazodone for agitation in dementia. Cochrane Database Syst Rev. 2004 Oct 18;(4):CD004990.
[5] Stormer E, von Moltke LL, Perloff MD, et al. P-glycoprotein interactions of nefazodone and trazodone in cell culture. J Clin Pharmacol. 2001;41(7):708-714.
[6] Zitron E, Kiesecker C, Scholz E, et al. Inhibition of cardiac herg potassium channels by the atypical antidepressant trazodone. Naunyn-Schmiedeberg's Arch Pharmacol. 2004;370(2):146-56.
[7] Yang J, Huang J, Pan Z, et al. Therapeutic potential of trazodone in trigeminal neuralgia based on inflammation and oxidative stress: an in vitro experimental study. Journal of Oral & Facial Pain and Headache. 2024;38(2):119-125.
[8] Arai M, Kent BA, et al. The effects of acute trazodone administration on sleep in mice. Sleep Advances. 2025;6:zpaf031.
[9] Albert-Gasco H, Smith HL, Alvarez-Castelao B, et al. Trazodone rescues dysregulated synaptic and mitochondrial nascent proteomes in prion neurodegeneration. Brain. 2024;147(2):649-664.
[10] Boboc I, Chirea A, Gheorman V, et al. Investigating the neuroprotective and neuroregenerative effect of trazodone regarding behavioral recovery in a BL6C57 mice stroke model. Current Health Sciences Journal. 2023 Apr-Jun;49(2):210-219.