In a patient with ongoing depression after three days of aripiprazole (Abilify) 5 mg daily and mirtazapine 15 mg at bedtime, which medication should be increased?

Increase Mirtazapine First

After only 3 days of treatment, neither medication has had adequate time to reach therapeutic effect—you should increase mirtazapine to 30 mg at bedtime and wait the full 6-8 weeks required to assess antidepressant response before making further changes. 1, 2

Why This Timeline Matters

Mirtazapine Requires 6-8 Weeks for Adequate Assessment

• The FDA label clearly states that dose changes should not be made in intervals of less than 1-2 weeks, and the American College of Physicians recommends assessing therapeutic response within 1-2 weeks but requires 6-8 weeks to determine if adequate response has occurred 1, 2
• Your current 15 mg dose is the FDA-recommended starting dose, but many patients require titration to 30-45 mg for full antidepressant effect 2
• Mirtazapine takes 14 days to reach steady-state plasma concentrations, with 4-fold accumulation occurring over this period 3

Aripiprazole Also Requires Extended Time

• Aripiprazole requires at least 1-2 weeks, and sometimes up to 4 weeks, to reach full therapeutic effect 4
• Steady-state concentrations are not attained until 14 days of dosing 4
• At 3 days, you are far too early to assess either medication's efficacy

Specific Dosing Algorithm

Step 1: Increase Mirtazapine Now

• Increase mirtazapine from 15 mg to 30 mg at bedtime immediately 2
• The FDA-approved dosing is 15 mg starting dose with increases up to 45 mg maximum 2
• The 15 mg dose you started is subtherapeutic for many patients with major depression 5

Step 2: Maintain Aripiprazole at Current Dose

• Keep aripiprazole at 5 mg daily for now 6
• While 5 mg is below the optimal 10 mg/day dose that shows highest response rates in schizophrenia studies, it may have augmentation effects in depression 6
• The threshold for clinical effect in psychotic disorders is between 5-10 mg/day 6

Step 3: Reassess at 6-8 Weeks

• If inadequate response at 6-8 weeks on mirtazapine 30 mg, increase to 45 mg maximum 2
• Only after achieving adequate mirtazapine dosing and waiting 6-8 weeks should you consider adjusting aripiprazole 1
• If still inadequate response, consider increasing aripiprazole to 10 mg (the optimal dose for augmentation based on schizophrenia data showing highest response rates) 6

Critical Pitfalls to Avoid

Don't Make Premature Changes

• Three days is far too early to judge efficacy of either medication 1, 4
• Making changes before 6-8 weeks prevents you from knowing which medication is actually working 1
• The acute treatment phase for depression lasts 6-12 weeks, and stopping or changing at 3 weeks falls far short of completing this phase 1

Mirtazapine-Specific Advantages for Your Patient

• Mirtazapine has faster onset of action than SSRIs like fluoxetine, paroxetine, and sertraline 1
• It is particularly effective for depression with insomnia or sleep disturbances, which are common in depression 1, 5
• It promotes sleep, appetite, and weight gain, making it suitable for patients with depression accompanied by insomnia or weight loss 1

Monitor for Common Side Effects

• Mirtazapine: somnolence/sedation, increased appetite, weight gain, dry mouth 1, 2
• Aripiprazole: headache, agitation, anxiety, insomnia, akathisia 7, 4
• If excessive sedation occurs with mirtazapine 30 mg, this is expected and often improves with continued use 3

Why Not Increase Aripiprazole First?

• Aripiprazole as augmentation in depression typically uses 5-15 mg doses, and you're already at the lower therapeutic threshold 8, 6
• The primary antidepressant (mirtazapine) should be optimized first before adjusting the augmentation agent 1
• Increasing aripiprazole before adequately dosing mirtazapine creates unnecessary polypharmacy without addressing the undertreated primary medication 2