Is Trazodone (an antidepressant medication) less sedating at increasing doses?

From the Guidelines

Trazodone tends to become less sedating at higher doses, which may seem counterintuitive, as its antidepressant effects become more prominent through serotonin reuptake inhibition and 5-HT2A/5-HT2C receptor antagonism, while the sedating effects don't increase proportionally. At lower doses (25-100mg), trazodone primarily blocks histamine and alpha-1 receptors, causing sedation that makes it useful for insomnia, as seen in studies where 60% of patients experienced daytime sedation as a side effect 1. However, as the dose increases (150mg and above), the sedating effects don't increase proportionally, and patients may notice that when titrating up to antidepressant doses (typically 150-300mg daily), the medication feels less sedating than when they started at lower doses.

Key Points to Consider

• The mean effective dose of trazodone in reducing nightmare frequency was 212 mg/day, with 60% of patients experiencing some side effect, particularly daytime sedation or dizziness 1.
• The sedating effects of trazodone are more pronounced at lower doses, making it useful for insomnia, while higher doses are more effective for depression, with a changing side effect profile 1.
• Patients using trazodone specifically for sleep may benefit from staying at lower doses (50-100mg), while those using it for depression may need to adjust to the changing side effect profile as they reach therapeutic antidepressant doses.

Clinical Implications

• When prescribing trazodone, clinicians should be aware of the potential for sedation at lower doses and the changing side effect profile at higher doses.
• Patients should be closely monitored for side effects, particularly daytime sedation, dizziness, and priapism, and the dose should be adjusted accordingly.
• The pharmacological properties of trazodone make it a useful medication for both insomnia and depression, but clinicians should be aware of the potential for varying side effects at different doses, as reported in studies 1.

From the Research

Trazodone Sedation at Increasing Doses

• The sedating effects of Trazodone at increasing doses are not entirely clear, but some studies provide insight into its pharmacological properties and therapeutic use 2, 3, 4, 5, 6.
• According to a study published in 1987, Trazodone may be more effective at lower than maximal doses, and some studies that used high dosages reported poorer therapeutic responses than those that employed more conservative dosages 2.
• A 1994 review of Trazodone's pharmacology and therapeutic use suggests that the drug has antidepressant, anxiolytic, and hypnotic activity, but the incidence of drowsiness is commonly reported, particularly at higher doses 3.
• A 2012 study on the rediscovery of Trazodone for the treatment of major depressive disorder notes that the most common adverse effects reported with Trazodone are drowsiness, headache, dizziness, and dry mouth, but does not specifically address the relationship between dose and sedation 4.
• A 2018 study evaluating the dose-dependent mechanism of action of Trazodone found that low doses of the drug (typically 50 mg daily) should suffice to block specific receptors responsible for the hypnotic effect, while higher doses are required for an antidepressant effect 6.
• Overall, the evidence suggests that Trazodone's sedating effects may not necessarily increase at higher doses, and that the drug's therapeutic efficacy and side effect profile may be optimized at lower doses 2, 6.

Comparison of Trazodone to Other Antidepressants

• Trazodone has been compared to other antidepressants, including tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), and serotonin-noradrenaline reuptake inhibitors (SNRIs), in terms of its efficacy and tolerability 3, 4, 5.
• A 1981 review of Trazodone's pharmacological properties and therapeutic use notes that the drug has an overall therapeutic efficacy comparable to imipramine and amitriptyline, but causes fewer anticholinergic side effects than TCAs 5.
• A 2012 study on the rediscovery of Trazodone for the treatment of major depressive disorder suggests that the drug may be an effective and well-tolerated alternative to other antidepressants, particularly in patients who are unresponsive to or cannot tolerate therapy with other agents 4.

Therapeutic Use of Trazodone

• Trazodone is approved and marketed for the treatment of major depressive disorder (MDD) in adult patients, and has also been used off-label for the treatment of sleep disorders and anxiety 3, 4, 6.
• The drug's therapeutic efficacy and safety profile make it a useful option for patients with MDD, particularly those who are elderly or have comorbid medical conditions 3, 4, 5.
• Recent studies have focused on the development of new formulations of Trazodone, including a prolonged-release once-a-day formulation, which may provide improved tolerability and patient compliance 4.