Trazodone as an Effective Medicine in the Therapy of Depression and Insomnia

Mechanism of Action

Trazodone belongs to the SARI group (serotonin antagonists and re-uptake inhibitors), selectively inhibiting serotonin reuptake at the synapse while also acting as an antagonist of serotonin receptors 5-HT_2A. It also antagonizes several other monoaminergic receptors, such as 5-HT_2C or α₁, while its anticholinergic effect remains minimal.

The effect of trazodone depends on the dose administered. At low doses, it mainly affects the 5-HT_2A, H₁, and α₁ receptors, and thus primarily has a hypnosedative effect. At 3-5 times the dose, it blocks the serotonin transporter (SERT) and adds its antidepressant effect. A recent study showed that at a dosage of 150 mg of trazodone per day, up to 90% of SERT is blocked. The fact that its antidepressant effect increases with higher doses supports the theory that SERT blockade is more significant in the treatment of depression than the influence on other receptors. As a result of the inhibition of the 5-HT_2A and 5-HT_2C receptors, which persists even at high doses of trazodone, sleep disorders, sexual dysfunctions, and anxiety are reduced, which is a significant advantage compared to antidepressants from the SSRI or SNRI groups, which may cause these conditions.

Trazodone in Clinical Practice

Treatment with trazodone is usually initiated at a dose of 75-150 mg/day and then increased to 150-300 mg/day. The medicine is available on the Czech market in the form of tablets with controlled (gradual) release and extended-release tablets. Both modifications of the product's pharmacokinetics prevent significant and rapid increases in plasma concentration of the medicine (peak), which is associated with side effects. These include drowsiness and sedation, as well as headache, dizziness, and dry mouth during trazodone use. However, it is usually very well tolerated.

Several clinical studies have demonstrated a comparable antidepressant effect of trazodone with tricyclic antidepressants, SSRIs, or SNRIs. Studies also showed that it is significantly more effective in reducing sleep disorders compared to them. However, it is sometimes prescribed not primarily as an antidepressant but for the treatment of insomnia, which may accompany depression. Patients often use it in lower doses in combination with other antidepressants, and its multimodal effect is thus not utilized. An important change in practice was brought by the extended-release tablets, which allow the medicine to be taken only once a day, usually before sleep. This ensures better compliance of depressive patients and reduces the tendency for daytime drowsiness.

As mentioned above, trazodone has a positive effect in the treatment of comorbidities and disorders that may occur simultaneously with depression. These include anxiety, post-traumatic stress disorder, bulimia, fibromyalgia, sexual dysfunctions, neurocognitive disorders, akathisia associated with antipsychotic use, and especially insomnia.

The Potential of Trazodone in Insomnia Therapy

Several studies have confirmed the hypnotic effect of trazodone in patients suffering from insomnia, whether primary or related to depression. Its efficacy in treating sleep disorders has also been demonstrated in patients with dementia, anxiety disorders, and post-traumatic stress disorder. A study comparing trazodone with quetiapine, which evaluated overall sleep duration and the number of nighttime awakenings, recorded greater efficacy of trazodone compared to quetiapine.

According to a recently conducted observational study, it might also be effective in the treatment of insomnia and nightmares in patients with advanced-stage cancer, and several case reports even suggest its potential in the therapy of narcolepsy and cataplexy.

Summary and Conclusion

Trazodone is among the effective and well-tolerated antidepressants. Its multimodal effect is fully utilized at doses of 150-300 mg/day, where it has both antidepressant and hypnosedative effects. Treatment with trazodone is very advantageous for depressive patients suffering from insomnia.

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Source: Cuomo A., Ballerini A., Bruni A. C. et al. Clinical guidance for the use of trazodone in major depressive disorder and concomitant conditions: pharmacology and clinical practice. Rivista di Psichiatria 2019; 54 (4): 137-149, doi: 10.1708/3202.31796.