Initiate duloxetine at the standard starting dose as the preferred first-line antidepressant for this patient

Because its dual serotonin-norepinephrine mechanism addresses both the depressive symptoms and the fatigue commonly seen in hepatic disease. The SNRI class has demonstrated hepatoprotective properties in clinical studies, and duloxetine's predictable pharmacokinetics make it safe even in moderate hepatic impairment. The dual mechanism offers broader symptom coverage than SSRIs, making it particularly well-suited for patients with comorbid medical conditions. Duloxetine can be initiated at the standard starting dose without dose adjustment in Child-Pugh B cirrhosis. Duloxetine is contraindicated in patients with substantial hepatic impairment, including those with Child-Pugh B or C cirrhosis.

Start a low-dose tricyclic antidepressant such as nortriptyline with therapeutic drug level monitoring

Because tricyclics undergo simple hepatic metabolism and their well-established pharmacokinetic profiles make them predictable even in liver disease. Nortriptyline has a defined therapeutic window that can be monitored through serum drug levels, providing an additional safety measure in patients with altered hepatic function. The sedating properties of tricyclic antidepressants would also address the patient's insomnia without requiring a separate sleep medication. Tricyclic antidepressants have the longest track record of safe use in medically complex populations. Tricyclic antidepressants undergo extensive hepatic metabolism and have a narrow therapeutic index, making them particularly problematic in patients with hepatic impairment.

Initiate an SSRI such as sertraline or escitalopram at a reduced starting dose with careful titration for hepatic impairment

SSRIs as a class have a wider therapeutic index than tricyclic antidepressants, and sertraline in particular has a more favorable hepatic safety profile with less CYP enzyme inhibition than some other SSRIs. Dose reduction and slower titration are necessary because hepatic impairment reduces drug clearance and increases the risk of elevated plasma concentrations and serotonergic side effects. Close monitoring of liver function tests during initiation and titration is an essential component of the treatment plan for this patient.

Initiate bupropion at standard dosing as the safest choice given its primarily renal elimination pathway

Because it is primarily renally eliminated, bypassing hepatic metabolism entirely and eliminating any concern about worsening liver function. Its activating properties would address the patient's fatigue and concentration difficulties more effectively than serotonergic agents, making it particularly well-suited for her symptom profile. Bupropion also avoids the sexual side effects and weight gain associated with SSRIs, which are important quality-of-life considerations in patients already managing a chronic medical condition. Standard dosing can be used because the renal elimination pathway is unaffected by hepatic disease. Bupropion is extensively metabolized by the liver, primarily through the CYP2B6 enzyme, and is not primarily renally eliminated.