However, a side effect of trazodone, orthostatic hypotension, which may cause dizziness and increase the risk of falling, can have devastating consequences for elderly patients; thus, this side effect, along with sedation, often makes trazodone less acceptable for this population, compared with newer compounds that share its lack of anticholinergic activity but not the rest of its side-effect profile. Still, trazodone is often helpful for geriatric patients with depression who have severe agitation and insomnia.Trazodone is usually used at a dosage of 150 to 300 mg/day for the treatment of depression. Lower doses have also been used to augment other antidepressants, or when initiating therapy. Higher doses up to 600 mg/day have been used in more severe cases of depression, for instance in hospitalized patients. Trazodone is usually administered multiple times per day, but once-daily administration may be similarly effective. Anxiety disorders
Trazodone is often used in the treatment of anxiety disorders such as generalized anxiety disorder, panic disorder, post-traumatic stress disorder (PTSD), and obsessive–compulsive disorder (OCD). However, use of trazodone in anxiety disorders is off-label and evidence of its effectiveness for these indications is variable and limited. Benefits for OCD appear to be mild. Besides anxiety, trazodone has been used to treat sleep disturbances and nightmares in PTSD. Trazodone is often used as an alternative to benzodiazepines in the treatment of anxiety disorders. Insomnia
Low-dose trazodone is used off-label in the treatment of insomnia and is considered to be effective and safe for this indication. It may also be used to treat antidepressant-related insomnia.
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.