What are the possible medication adjustment options for a patient with treatment-resistant depression on duloxetine (60 mg) and Abilify (5 mg), with a history of ineffective SSRI treatment and concomitant aspirin therapy?

Medication Adjustment Options for Treatment-Resistant Depression

For this patient with treatment-resistant depression on duloxetine 60 mg and aripiprazole 5 mg augmentation who has failed multiple SSRIs, the most evidence-based options are: (1) increase aripiprazole to 10-15 mg for more robust augmentation, (2) switch duloxetine to a different mechanism antidepressant such as bupropion or mirtazapine, or (3) consider adding lithium augmentation. 1, 2, 3

Current Treatment Assessment

This patient meets criteria for treatment-resistant depression (TRD), defined as inadequate response to at least two antidepressants of different mechanisms at adequate doses and duration 1. The patient has failed:

• Three SSRIs (sertraline, citalopram, fluoxetine)
• Currently on duloxetine (SNRI) with inadequate response despite aripiprazole augmentation

The current aripiprazole dose of 5 mg is at the lower end of the therapeutic range for augmentation in depression 4, 2.

Primary Treatment Options

Option 1: Optimize Current Augmentation Strategy

Increase aripiprazole from 5 mg to 10-15 mg daily, as this remains within the FDA-approved augmentation range and aripiprazole has the strongest evidence for efficacy in TRD 2, 3. Aripiprazole augmentation is FDA-approved and has demonstrated superior efficacy compared to other augmentation strategies in multiple trials 5, 2.

• The therapeutic range for aripiprazole augmentation is 2-20 mg daily, with most patients responding to 10-15 mg 4
• This approach avoids the risks of switching antidepressants and potential withdrawal symptoms 6
• Monitor for akathisia, weight gain, and metabolic effects as dose increases 4

Option 2: Switch Antidepressant Class

Switch from duloxetine to bupropion or mirtazapine using a cross-taper approach, as these represent different mechanisms of action (dopamine/norepinephrine reuptake inhibition and alpha-2 antagonism, respectively) 1.

For switching from duloxetine:

• Gradually reduce duloxetine over 1-2 weeks to minimize discontinuation syndrome (dizziness, nausea, paresthesias, irritability) 6
• The STAR*D trial showed that switching to a different antidepressant class resulted in remission in approximately 25% of patients who failed initial treatment 1
• Mirtazapine has demonstrated faster onset of action (within 2-4 weeks) compared to SSRIs and SNRIs 1

Important caveat: The patient is on aspirin 15 mg twice daily (likely 81 mg twice daily), which increases bleeding risk when combined with duloxetine 1, 6. This makes switching away from duloxetine potentially advantageous from a safety perspective.

Option 3: Add Lithium Augmentation

Add lithium carbonate starting at 300 mg daily, titrated to therapeutic levels (0.6-1.0 mEq/L) while continuing current regimen 2, 3.

• Lithium augmentation has extensive evidence for efficacy in TRD, second only to aripiprazole in terms of research support 2, 3
• Requires baseline and ongoing monitoring of renal function, thyroid function, and serum lithium levels 2
• May be particularly effective when combined with SNRIs like duloxetine 3

Secondary Considerations

Duloxetine Dose Escalation

Increasing duloxetine from 60 mg to 120 mg daily is NOT recommended as the primary strategy 6. The FDA label states there is no evidence that doses greater than 60 mg daily confer additional benefit for depression, and higher doses are associated with increased adverse effects 6. However, one study showed that patients who relapsed on duloxetine 60 mg daily had a 62% response rate when increased to 120 mg daily 7.

Combination Antidepressant Strategy

Adding bupropion or mirtazapine to duloxetine (rather than switching) is another option 2, 3:

• Bupropion 150-300 mg daily added to duloxetine provides complementary dopaminergic effects
• Mirtazapine 15-45 mg at bedtime added to duloxetine may improve sleep and appetite while providing different receptor activity
• This approach has moderate evidence but increases polypharmacy and side effect burden 2

Critical Safety Considerations

Serotonin Syndrome Risk

With any combination strategy involving duloxetine, monitor closely for serotonin syndrome, especially in the first 24-48 hours after dose changes 1, 6. Signs include:

• Mental status changes (agitation, confusion)
• Autonomic instability (tachycardia, labile blood pressure, hyperthermia)
• Neuromuscular symptoms (tremor, hyperreflexia, myoclonus)

Bleeding Risk with Aspirin

The combination of duloxetine and aspirin increases bleeding risk 1, 6. If continuing duloxetine, counsel the patient about signs of bleeding and consider monitoring for occult blood loss.

Discontinuation Syndrome

If switching from duloxetine, taper gradually over at least 1-2 weeks 6. Abrupt discontinuation causes dizziness, nausea, paresthesias, irritability, and anxiety in a significant proportion of patients 6.

Recommended Algorithm

1. First-line: Increase aripiprazole to 10-15 mg daily and reassess in 4-6 weeks 4, 2
2. If inadequate response: Switch to bupropion or mirtazapine using gradual cross-taper 1, 8
3. If partial response to step 1: Add lithium augmentation to current regimen 2, 3
4. If all fail: Consider referral for esketamine, ketamine, or electroconvulsive therapy 2, 3

The choice between these options should account for the patient's specific symptom profile, prior side effects, comorbidities, and the bleeding risk from aspirin co-administration 6.