Trazodone was the second-most prescribed agent for insomnia in the early 2000s, though most studies of trazodone for treatment of sleep disturbances have been in depressed individuals.Systematic reviews and meta-analyses published in the late 2010s, including a Cochrane review, found low-dose trazodone to be an effective medication for short-term treatment of insomnia both in depressed and non-depressed people. Trazodone slightly improves subjective sleep quality (SMD = –0.34 to –0.41) and reduces number of nighttime awakenings (MD = –0.31, SMD = –0.51). Conversely, it does not appear to affect sleep onset, total sleep time, time awake after sleep onset, or sleep efficiency. It appears to increase deep sleep, in contrast to certain other hypnotics. The quality of evidence of trazodone for short-term treatment of insomnia was rated as low to moderate. There is no evidence available at present to inform long-term use of trazodone in the treatment of insomnia.The benefits of trazodone for insomnia must be weighed against potential adverse effects such as morning grogginess, daytime sleepiness, cognitive and motor impairment, and postural hypotension, among others. Quality safety data on use of trazodone as a sleep aid are currently lacking.Trazodone is used at low doses in the range of 25 to 150 mg/day for insomnia. Higher doses of 200 to 600 mg/day have also been studied.The American Academy of Sleep Medicines 2017 clinical practice guidelines recommended against the use of trazodone in the treatment of insomnia due to inadequate evidence and due to harms potentially outweighing benefits.
Target occupancy studies
Studies have estimated occupancy of target sites by trazodone based on trazodone concentrations in blood and brain and on the affinities of trazodone for the human targets in question. Roughly half of brain 5-HT2A receptors are blocked by 1 mg of trazodone and essentially all 5-HT2A receptors are saturated at 10 mg of trazodone, but the clinically effective hypnotic doses of trazodone are in the 25–100 mg range. The occupancy of the serotonin transporter (SERT) by trazodone is estimated to be 86% at 100 mg/day and 90% at 150 mg/day. Trazodone may almost completely occupy the 5-HT2A and 5-HT2C receptors at doses of 100 to 150 mg/day. Significant occupancy of a number of other sites may also occur. However, another study estimated much lower occupancy of the SERT and 5-HT2A receptors by trazodone. Correspondence to clinical effects
Trazodone may act predominantly as a 5-HT2A receptor antagonist to mediate its therapeutic benefits against anxiety and depression. Its inhibitory effects on serotonin reuptake and 5-HT2C receptors are comparatively weak. In relation to these properties, trazodone does not have similar properties to selective serotonin reuptake inhibitors (SSRIs) and is not particularly associated with increased appetite and weight gain—unlike other 5-HT2C antagonists like mirtazapine. Moderate 5-HT1A partial agonism may contribute to trazodones antidepressant and anxiolytic actions to some extent as well.The combined actions of 5-HT2A and 5HT2C receptor antagonism with serotonin reuptake inhibition only occur at moderate to high doses of trazodone.