I am taking sertraline 100 mg and mirtazapine 15 mg for depression with mildly elevated liver enzymes; what dose adjustments or augmentation options can improve my depressive symptoms?

Optimizing Treatment for Depression with Sertraline and Mirtazapine

Primary Recommendation for Dose Adjustment

Increase sertraline to 150-200 mg daily as the first step, since you are currently on a moderate dose and approximately 38% of patients fail to respond at initial SSRI doses within 6-12 weeks. 1

• Sertraline can be safely titrated up to 200 mg daily in 50 mg increments at 1-2 week intervals if response remains inadequate 2
• Allow 6-8 weeks at each dose level to assess response before making further changes 2
• Your current mirtazapine 15 mg dose is appropriate and should be continued, as this combination (SSRI + mirtazapine) has demonstrated equivalent efficacy to switching strategies in treatment-resistant depression 1

Liver Enzyme Considerations

Your mildly elevated liver enzymes require monitoring but do not necessitate dose reduction at this stage, as both sertraline and mirtazapine are associated with reversible hepatotoxicity that resolves upon discontinuation. 3, 4

• Sertraline has one of the lowest incidences of drug-induced liver injury among antidepressants (0.03%), significantly lower than mirtazapine (which shows higher rates) 4
• Monitor liver function tests every 4-8 weeks during dose escalation 3
• Discontinue immediately if transaminases exceed 3 times the upper limit of normal or if you develop jaundice, nausea, fatigue, or abdominal pain 3, 5
• Mirtazapine-induced steatosis typically resolves rapidly after discontinuation if it occurs 5

Augmentation Options if Sertraline Optimization Fails

If depressive symptoms persist after 6-8 weeks at sertraline 200 mg, add cognitive behavioral therapy (CBT) rather than switching medications, as augmentation with CBT demonstrates superior efficacy compared to medication switches. 1, 2

Alternative Pharmacologic Augmentation Strategies (in order of preference):

1. Bupropion SR augmentation (150-300 mg daily) - demonstrated equivalent efficacy to other augmentation strategies in STAR*D trial with lower discontinuation rates due to adverse events compared to buspirone (12.5% vs 20.6%) 1

2. Aripiprazole augmentation (2-15 mg daily) - showed higher remission rates (55.4%) compared to bupropion augmentation (34.0%) in one trial, though this was a higher risk-of-bias study 1

3. Increase mirtazapine to 30-45 mg daily - the FDA-approved dosing range is 15-45 mg, with dose changes made in 1-2 week intervals 6. However, note that mirtazapine at higher doses may worsen liver enzyme elevations 4

Switching Strategy if Augmentation Fails

Switch to venlafaxine extended-release 75-225 mg daily if you fail to respond after optimizing sertraline and attempting augmentation, as one in four patients becomes symptom-free after switching medications. 1

• The STAR*D trial demonstrated no significant differences between switching to bupropion SR, sertraline, or venlafaxine extended-release 1
• Two smaller studies suggested venlafaxine may have superior response rates in treatment-resistant depression, though evidence is limited 1
• Allow at least 14 days washout when switching from mirtazapine to avoid serotonin syndrome 6

Critical Monitoring Requirements

Monitor for treatment-emergent suicidality weekly during the first month, especially after dose increases, as SSRIs carry FDA black box warnings with 14 additional cases per 1000 patients treated. 2

• Assess response using standardized depression rating scales at 4 weeks and 8 weeks 2
• Check liver function tests (AST, ALT, GGT, bilirubin) every 4-8 weeks during dose escalation 3
• Monitor for serotonin syndrome symptoms (confusion, agitation, tremor, hyperreflexia, diaphoresis, tachycardia) when combining sertraline with mirtazapine 2

Treatment Duration

Continue treatment for a minimum of 12-24 months after achieving remission, as meta-analysis of 31 trials demonstrates that continued antidepressant treatment significantly protects against relapse. 1, 2

Common Pitfalls to Avoid

• Do not switch medications prematurely - allow full 6-8 weeks at therapeutic doses before concluding treatment failure 2
• Do not abruptly discontinue sertraline - taper gradually to minimize discontinuation syndrome 2
• Do not combine with MAOIs - requires 14-day washout period 6
• Do not ignore liver enzyme trends - discontinue immediately if enzymes exceed 3x upper limit of normal 3