Priapism
A relatively rare side effect associated with trazodone is priapism, likely due to its antagonism at α-adrenergic receptors. More than 200 cases have been reported, and the manufacturer estimated that the incidence of any abnormal erectile function is about one in 6,000 male patients treated with trazodone. The risk for this side effect appears to be greatest during the first month of treatment at low dosages (i.e. <150 mg/day). Early recognition of any abnormal erectile function is important, including prolonged or inappropriate erections, and should prompt discontinuation of trazodone treatment. Spontaneous orgasms have also been reported with trazodone in men.Clinical reports have described trazodone-associated psychosexual side effects in women as well, including increased libido, priapism of the clitoris, and spontaneous orgasms. Others
Rare cases of liver toxicity have been observed, possibly due to the formation of reactive metabolites.Elevated prolactin concentrations have been observed in people taking trazodone. They appear to be increased by around 1.5- to 2-fold.Studies on trazodone and cognitive function are mixed, with some finding improvement, others finding no change, and some finding impairment.Trazodone does not seem to worsen periodic limb movements during sleep.Trazodone is associated with increased risk of falls in older adults. It has also been associated with increased risk of hip fractures in older adults. Pregnancy and lactation
Sufficient data in humans are lacking. Use should be justified by the severity of the condition to be treated. Overdose
There are reported cases of high doses of trazodone precipitating serotonin syndrome.
On the other hand, CYP2D6 genotype has not been found to predict trazodone or mCPP concentrations with trazodone therapy, although it did correlate with side effects like dizziness and prolonged corrected QT interval.Combination of trazodone with selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), or monoamine oxidase inhibitors has a theoretical risk of serotonin syndrome. However, trazodone has been studied in combination with SSRIs and seemed to be safe in this context. On the other hand, cases of excessive sedation and serotonin syndrome have been reported with the combinations of trazodone and fluoxetine or paroxetine. This may be due to combined potentiation of the serotonin system. However, it may also be related to the fact that fluoxetine and paroxetine are strong inhibitors of CYP2D6 and fluoxetine is additionally a weak or moderate inhibitor of CYP3A4. Accordingly, fluoxetine has been reported to result in increased levels of trazodone and mCPP by 1.31- to 1.65-fold and by 2.97- to 3.39-fold, respectively.Smokers have lower levels of trazodone and higher ratios of mCPP to trazodone. Trazodone levels were 30% lower in smokers and mCPP to trazodone ratio was 1.29-fold higher in smokers, whereas mCPP concentrations were not different between smokers and non-smokers. Smoking is known to induce CYP1A2, and this may be involved in these findings. Pharmacology
Pharmacodynamics
Trazodone is a mixed agonist and antagonist of various serotonin receptors, antagonist of adrenergic receptors, weak histamine H1 receptor antagonist, and weak serotonin reuptake inhibitor.