Which Is Better for Depression, Zoloft or Trazodone?

October 10, 2025 •

3 min read

According to a 2006 double-blind study, extended-release trazodone and sertraline (Zoloft) were comparably effective in treating major depressive disorder. However, choosing which is better for depression, Zoloft or trazodone, depends heavily on a patient's individual symptoms, side effect tolerance, and coexisting conditions.

Quick Summary

Zoloft (sertraline) and trazodone treat major depression but through different mechanisms. Zoloft is a standard SSRI, while trazodone is a SARI often used for depression with comorbid insomnia due to its sedating effects. Differences in side effect profiles, including sexual dysfunction and sedation, influence which drug is more suitable for a particular patient's needs and tolerability. The final choice rests on a doctor's evaluation of the specific symptoms.

Key Points

Mechanism of Action: Zoloft is an SSRI that primarily increases serotonin, while trazodone is a SARI that blocks multiple receptors, causing significant sedation at low doses.
Symptom Focus: Trazodone may be preferred for patients with depression accompanied by severe insomnia, while Zoloft is a standard choice for broader depressive and anxiety symptoms.
Sedation Level: Trazodone is highly sedating and often used for sleep, whereas Zoloft is generally more activating and can sometimes cause insomnia.
Sexual Side Effects: Patients concerned about or experiencing sexual dysfunction may prefer trazodone, which has a lower risk of this side effect compared to Zoloft.
Side Effect Tolerance: Gastrointestinal issues and sexual dysfunction are more common with Zoloft, while sedation and orthostatic hypotension are more common with trazodone.
Combination Potential: In some cases, a doctor may add a low dose of trazodone to a Zoloft regimen to specifically treat insomnia, though this requires careful medical supervision due to the risk of serotonin syndrome.
Personalized Choice: The best option is not universal. It is a decision that must be made with a healthcare provider based on a patient's full symptom profile and medical history.

Understanding the Antidepressant Classes

Zoloft (sertraline) is a Selective Serotonin Reuptake Inhibitor (SSRI), commonly used as a first-line treatment for depression. Trazodone, a Serotonin Antagonist and Reuptake Inhibitor (SARI), was originally approved as an antidepressant but is often prescribed off-label for insomnia due to its sedative effects.

Zoloft (Sertraline): The SSRI Standard

Zoloft works by blocking the reabsorption of serotonin in the brain, increasing the amount of available serotonin which is thought to improve mood. It is FDA-approved for several conditions, including major depressive disorder (MDD), OCD, panic disorder, PTSD, and social anxiety disorder. Common side effects include gastrointestinal issues, sleep disturbances, and a significant risk of sexual dysfunction. Zoloft can be activating, which may help with energy but could also worsen anxiety or insomnia in some individuals. Due to its effectiveness and history, it is often a first-line treatment for depression.

Trazodone: A SARI with Sedating Effects

Trazodone's effects are dose-dependent. At lower doses (50–150 mg), its sedative properties are prominent, making it useful for insomnia. At higher antidepressant doses (150–600 mg), it also inhibits serotonin reuptake, particularly benefiting patients with sleep problems.

Key Characteristics of Trazodone

Trazodone is known for causing drowsiness, which can help with depression-related insomnia but may not be suitable for those who need to remain alert. It is associated with a lower incidence of sexual dysfunction compared to SSRIs like Zoloft. However, it can cause dizziness upon standing due to its effects on certain receptors. A very rare but serious side effect is a prolonged erection (priapism).

Choosing Between Zoloft and Trazodone

Deciding between Zoloft and trazodone requires a conversation with a healthcare provider, taking into account symptoms, medical history, and treatment goals. A 2006 study indicated that both were similarly effective for major depressive symptoms, but they have different side effect profiles.

Factors to Consider

Trazodone may be more suitable for patients experiencing both depression and insomnia, while Zoloft might be preferred for those dealing with fatigue or who need to maintain energy levels. Trazodone offers an alternative for individuals unable to tolerate the sexual side effects commonly associated with SSRIs, though its sedating effect could be a drawback for some. A doctor might sometimes prescribe a low dose of trazodone alongside Zoloft to address insomnia, but this combination needs careful monitoring for serotonin syndrome. A patient's medical history, such as existing heart conditions, can also influence the choice due to potential drug interactions or effects.

Comparison Table: Zoloft vs. Trazodone


Feature	Zoloft (Sertraline)	Trazodone
Drug Class	Selective Serotonin Reuptake Inhibitor (SSRI)	Serotonin Antagonist and Reuptake Inhibitor (SARI)
Primary Use	First-line treatment for MDD, OCD, panic disorder, and more	FDA-approved for MDD, but commonly used off-label for insomnia
Mechanism	Inhibits serotonin reuptake	Inhibits serotonin reuptake; antagonizes 5-HT2A, H1, and α1 receptors
Sedation Profile	Generally activating; can cause insomnia	Significantly sedating, especially at lower doses
Sexual Side Effects	Higher risk of sexual dysfunction	Lower risk of sexual dysfunction
Key Side Effects	Nausea, diarrhea, insomnia, anxiety, sexual dysfunction, tremor	Drowsiness, dizziness, dry mouth, orthostatic hypotension, rare priapism
Average User Rating	Higher (7.3/10 on Drugs.com)	Lower (6.3/10 on Drugs.com)

Conclusion

Neither Zoloft nor trazodone is universally "better" for depression; both are effective with different profiles. Zoloft is a standard SSRI used for various conditions, while trazodone, also an antidepressant, is particularly helpful for depression with insomnia or for patients who experience sexual side effects with SSRIs. The optimal choice is highly individualized and determined by a healthcare professional based on specific symptoms, side effect tolerance, and medical history. Additional comparison information is available on {Link: Drugs.com https://www.drugs.com/compare/trazodone-vs-zoloft}.

Frequently Asked Questions

A 2006 study found both to be equally effective for reducing depressive symptoms. The better option depends on a patient's specific symptoms and tolerance for side effects, as they have different pharmacological profiles.

Yes, but only under strict medical supervision due to an increased risk of serotonin syndrome, a potentially dangerous condition. Low-dose trazodone is sometimes used with Zoloft to specifically manage insomnia.

Trazodone is often preferred for patients with coexisting depression and insomnia because of its potent sedative effects, especially when taken at bedtime.

Trazodone has a lower risk of causing sexual dysfunction compared to Zoloft. Sexual side effects are a common issue with SSRIs like Zoloft.

Yes, daytime drowsiness is a common side effect of trazodone, particularly at the higher doses needed for its antidepressant effects. This can impact daily activities, and Zoloft may be a better choice for those needing to stay alert.

Zoloft is a selective serotonin reuptake inhibitor (SSRI), primarily increasing serotonin by blocking reabsorption. Trazodone is a serotonin antagonist and reuptake inhibitor (SARI), which both inhibits serotonin reuptake and blocks certain serotonin receptors, causing additional sedative effects.

Zoloft is generally more suitable for patients who need to maintain daytime alertness, as it has a more activating profile. Trazodone's sedating effects make it a poor choice for those who cannot tolerate drowsiness during the day.