What to do for a patient with ongoing depression on Remeron (mirtazapine) 15 mg and Sertraline (selective serotonin reuptake inhibitor) 50 mg?

Management of Treatment-Resistant Depression on Mirtazapine 15 mg and Sertraline 50 mg

For a patient with ongoing depression on mirtazapine 15 mg and sertraline 50 mg, the most evidence-based approach is to optimize the sertraline dose first by increasing to 100-200 mg daily, as both medications are currently at subtherapeutic doses. 1, 2

Dose Optimization Strategy

Sertraline Dose Escalation (First Priority)

• Increase sertraline from 50 mg to 100 mg daily immediately 1, 2
  • 50 mg is the starting dose, not necessarily the optimal therapeutic dose 1
  • The therapeutic range is 50-200 mg/day, with most patients requiring higher doses for adequate response 1, 3
  • Evidence shows that 60% of initial non-responders achieve response when continuing treatment at 100 mg through week 8 2
  • If inadequate response after 2-4 weeks at 100 mg, increase to 150 mg, then 200 mg at weekly intervals 1

Critical caveat: Avoid jumping directly to 200 mg, as one study showed lower response rates (56%) at 200 mg compared to continuing 100 mg (70%) in sertraline non-responders 2

Mirtazapine Dose Adjustment (Second Priority)

• Increase mirtazapine from 15 mg to 30-45 mg daily 4, 5
  • The effective dose range is 15-45 mg, with 15 mg being the starting dose 4, 5
  • Higher doses (30-45 mg) provide greater noradrenergic effects and may enhance antidepressant efficacy 4
  • Paradoxically, 15 mg may be more sedating than higher doses due to predominant antihistamine effects at lower doses 4
  • Allow 1-2 weeks between dose adjustments due to mirtazapine's long half-life 5

Timeline for Assessment

Wait a full 8 weeks from initiation before declaring treatment failure 2

• Substantial increases in response rates occur between weeks 6-8 of treatment 2
• Both sertraline and mirtazapine require 2-4 weeks for onset of action, with full efficacy at 4-6 weeks 1, 4, 5
• Mirtazapine may show earlier improvement (1-2 weeks) compared to SSRIs 6, 4

Combination Therapy Rationale

The current combination of sertraline plus mirtazapine is pharmacologically sound 6

• Mirtazapine has been shown to be safe in combination with SSRIs 6
• This combination provides complementary mechanisms: SSRI action plus enhanced norepinephrine/serotonin release from mirtazapine's alpha-2 blockade 4, 5
• Sertraline has lower risk of QTc prolongation compared to citalopram/escitalopram, making it preferable for combination therapy 6

Safety Monitoring

Monitor for serotonin syndrome when using this combination 6

• Watch for mental status changes, neuromuscular hyperactivity (tremors, clonus), and autonomic instability 6
• Risk is present but manageable when combining non-MAOI serotonergic agents 6
• Symptoms typically arise within 24-48 hours after dose changes 6

Common adverse effects to anticipate:

• Nausea, dizziness, headache, insomnia from sertraline 6
• Sedation, increased appetite, weight gain from mirtazapine 4, 5
• Sexual dysfunction more likely with sertraline than mirtazapine 6

Alternative Strategies if Optimization Fails

If inadequate response after 8 weeks at optimized doses (sertraline 150-200 mg + mirtazapine 30-45 mg):

• Consider switching to venlafaxine or bupropion as monotherapy 6
• The STAR*D trial showed that 25% of patients who failed initial SSRI therapy achieved remission when switched to bupropion, sertraline, or venlafaxine 6
• Venlafaxine showed superior efficacy to fluoxetine in some studies for treatment-resistant depression 6

Avoid premature medication switching 2

• 70% of sertraline non-responders at week 6 eventually responded by continuing treatment through week 8 2
• Extended duration of treatment is as effective as augmentation strategies in many cases 2