Which antidepressants are hardest on the liver? A Comprehensive Guide

October 11, 2025 •

3 min read

Antidepressant-induced liver injury, while rare, can range from mild enzyme elevations to severe liver failure in some cases. Patients and healthcare providers must be aware of potential risks. This guide explores the medications with documented higher risks and addresses the key question, which antidepressants are hardest on the liver?

Quick Summary

Certain antidepressants, including nefazodone, older MAOIs, and some TCAs, have a higher reported risk of severe liver injury. Newer agents like duloxetine also pose a small but notable risk, while SSRIs are generally safer regarding hepatotoxicity.

Key Points

Nefazodone Poses Highest Risk: Nefazodone, largely withdrawn, has a black box warning for potentially fatal liver failure.
Older MAOIs are More Hepatotoxic: Older MAOIs like phenelzine and isocarboxazid are linked to rare but severe liver damage.
TCAs Carry Higher Risk than Newer Generations: Older tricyclic antidepressants like imipramine and amitriptyline are more often associated with liver issues compared to SSRIs or most SNRIs.
Duloxetine Requires Caution: The SNRI duloxetine has documented liver injury cases, with increased risk for patients with pre-existing liver disease or heavy alcohol use.
SSRIs Have the Lowest Hepatotoxicity Risk: Selective Serotonin Reuptake Inhibitors are generally the safest class regarding liver toxicity.
Liver Injury is Often Idiosyncratic: DILI is often not dose-dependent and can occur unpredictably.
Monitoring is Crucial for At-Risk Patients: Patients with pre-existing liver conditions or on high-risk medications may need regular liver function tests.

Understanding Drug-Induced Liver Injury (DILI)

Drug-Induced Liver Injury (DILI) is an adverse reaction to a medication that can harm the liver. It is often an unpredictable reaction not directly related to the drug dose. While the liver is equipped to process drugs, some individuals are more susceptible to DILI. Although most antidepressants are generally safe for the liver, certain ones have been linked to a higher rate of severe liver damage, leading to warnings or market withdrawal.

Antidepressants with the Highest Risk Profile

Nefazodone (Formerly Serzone)

Nefazodone is notably associated with severe hepatotoxicity, including acute liver failure. Due to reports of serious and sometimes fatal liver injury, it was withdrawn from the market in many countries. A 'black box' warning about the potential for serious liver damage remains on its generic version in the United States. The risk of severe liver damage from Nefazodone is estimated at 1 in 250,000 to 300,000 patient-years {Link: Dr. Oracle https://www.droracle.ai/articles/32359/can-sertraline-cause-liver-all-to-go-up}.

Older Monoamine Oxidase Inhibitors (MAOIs)

Older MAOIs have been linked to liver injury, with some being withdrawn. Phenelzine (Nardil) and Tranylcypromine (Parnate) have been associated with rare cases of acute liver injury. Isocarboxazid (Marplan) can cause temporary increases in liver enzymes and is a suspected rare cause of liver injury.

Tricyclic Antidepressants (TCAs)

Older TCAs like imipramine and amitriptyline are linked more often to liver toxicity than newer antidepressants.

Antidepressants with Notable, but Less Frequent, Risk

Duloxetine (Cymbalta)

Duloxetine (an SNRI) has been associated with rare cases of acute liver injury. Severe cases, including liver failure, have occurred, particularly in those with existing liver disease or alcohol use.

Venlafaxine (Effexor)

Venlafaxine, an SNRI, has also been associated with rare apparent liver injury, usually self-limiting, but severe reactions are reported.

Bupropion (Wellbutrin)

Bupropion may cause temporary enzyme increases and rare acute liver injury. Risk of side effects is higher in patients with severe hepatic cirrhosis.

Antidepressants Generally Considered Safer for the Liver

Selective Serotonin Reuptake Inhibitors (SSRIs)

SSRIs are generally low risk for severe liver damage, although rare reactions are possible. This includes Citalopram, Escitalopram, Sertraline, and Fluoxetine.

Moclobemide (Reversible MAOI)

Moclobemide has a low incidence of liver toxicity.

Antidepressant Hepatotoxicity Comparison


Antidepressant Class	Examples	Relative Hepatotoxicity Risk	Notes
Withdrawn/High Risk	Nefazodone (Serzone), Iproniazid	Highest	Nefazodone carries a black box warning; Iproniazid withdrawn due to high risk.
Older MAOIs	Phenelzine (Nardil), Isocarboxazid (Marplan)	High	Rare but potentially severe or fatal liver injury reported.
Older TCAs	Imipramine, Amitriptyline	Moderate	Higher risk compared to newer antidepressants.
SNRIs	Duloxetine (Cymbalta), Venlafaxine (Effexor)	Low-to-Moderate	Rare clinically apparent injury; risk elevated with underlying liver disease for duloxetine.
Atypical	Bupropion (Wellbutrin)	Low-to-Moderate	Rare cases of acute injury; enzyme elevations can occur.
SSRIs	Sertraline, Fluoxetine, Escitalopram, Citalopram	Lowest	Generally safe, but rare idiosyncratic reactions possible.

How Healthcare Providers Manage the Risk

Healthcare providers manage the risk through patient assessment, LFT monitoring before and during treatment (especially with higher-risk drugs), educating patients on liver injury signs, and prompt discontinuation if DILI is suspected. Early detection often leads to reversible damage.

Conclusion

Serious liver injury from antidepressants is uncommon, but certain medications, especially nefazodone and older irreversible MAOIs, pose a higher risk. Newer classes like SSRIs are generally safer. Patients with pre-existing liver disease or on multiple medications need careful consideration. Communicating with a healthcare provider is essential to balance benefits and risks, ensure monitoring, and address liver health concerns. Discussing lower-risk options and using routine monitoring are important steps.

For more in-depth information on drug-induced liver injury, consult {Link: NIH's LiverTox resource https://www.ncbi.nlm.nih.gov/books/NBK548584/}.

Frequently Asked Questions

No, clinically significant liver damage from antidepressants is rare. It can range from asymptomatic enzyme elevations to, in very rare cases, severe or fatal liver failure.

Yes, certain drug interactions can increase the risk of liver injury. It is crucial to inform your doctor about all medications, supplements, and herbal remedies you take.

Symptoms of liver injury include jaundice (yellowing skin/eyes), dark urine, pale stools, unexplained nausea, vomiting, abdominal pain, fever, and unusual fatigue or weakness.

Yes, risk factors can include advanced age, genetics, pre-existing liver disease, and heavy alcohol use. Patients taking multiple medications may also be at higher risk.

Liver injury is often idiosyncratic and not directly dose-dependent, meaning it's an unpredictable reaction unrelated to the dose. However, some cases have been reported following a dose change.

If liver injury is suspected or detected, the antidepressant is promptly discontinued. Most cases are reversible when detected early and the drug is stopped.

While all antidepressants carry some risk, Selective Serotonin Reuptake Inhibitors (SSRIs) like citalopram, escitalopram, and sertraline are generally considered to have the lowest hepatotoxicity potential. However, safety depends on individual patient factors.

No, the risk varies. The older, irreversible MAOIs like phenelzine are associated with rare but potentially severe injury, while the newer, reversible MAOI moclobemide is reported to have very low liver toxicity.