What is the best next line of medication for a patient with anxiety and Major Depressive Disorder (MDD) who has failed mirtazapine and has a history of not tolerating trazodone or fluoxetine?

Best Next-Line Medication After Mirtazapine Failure

Switch to sertraline 50-200 mg daily as the next-line treatment for this patient with MDD and anxiety who has failed mirtazapine and does not tolerate trazodone or fluoxetine. 1

Primary Recommendation: Sertraline

• Sertraline is recommended as a first-line SSRI alternative, demonstrating equivalent efficacy across MDD and anxiety disorders with robust evidence in multiple double-blind, placebo-controlled trials. 1

• Sertraline shows similar improvements in health-related quality of life, work functioning, and social functioning compared to other SSRIs, making it an appropriate choice given the patient's prior SSRI intolerance was specific to fluoxetine. 1

• Approximately 25% of patients achieve remission after switching to another SSRI, supporting a trial of sertraline despite previous fluoxetine failure. 1

• The therapeutic dose range is 50-200 mg daily, with adequate trial duration of at least 4 weeks at therapeutic dose before determining treatment failure. 2

Alternative Option: Venlafaxine (SNRI)

• Venlafaxine may offer advantages for patients with prominent anxiety symptoms, with limited evidence suggesting superior efficacy to fluoxetine specifically for anxiety in the context of depression. 2, 1

• The therapeutic dose range is 75-225 mg daily; doses below 75 mg are subtherapeutic and inadequate for treating either depression or anxiety. 2

• Venlafaxine demonstrates superior efficacy compared to fluoxetine specifically for treating anxiety symptoms in patients with comorbid depression and anxiety. 2

• Common pitfall: Starting venlafaxine at 37.5 mg and leaving it there—this dose is insufficient and may worsen anxiety symptoms. 2

Third Option: Bupropion Augmentation

• Adding bupropion SR 150-300 mg to the existing mirtazapine (if you choose to continue it) is a recommended augmentation strategy, with bupropion decreasing depression severity more than buspirone augmentation. 2

• Bupropion has equivalent efficacy to sertraline when switching from failed initial antidepressant therapy and shows similar efficacy for depression with anxiety. 1

• Important caveat: Bupropion is ineffective for PTSD, so if PTSD symptoms are present, this would not be the optimal choice. 1

• Bupropion has no appreciable activity on serotonin and works through norepinephrine and dopamine mechanisms, offering a distinct pharmacological profile. 3

• The maximum dose is 450 mg/day for immediate-release and 400 mg/day for sustained-release formulations, with gradual titration required due to seizure risk. 3

Treatment Algorithm

Step 1: Switch to Sertraline

• Start sertraline 50 mg daily, titrate to 100-200 mg based on response and tolerability. 2, 1
• Reassess after 4-6 weeks at therapeutic dose. 2

Step 2: If Inadequate Response to Sertraline

• Switch to venlafaxine ER 75 mg daily, titrate to 150-225 mg daily. 2
• Ensure minimum 4 weeks at therapeutic dose before declaring treatment failure. 2

Step 3: If Both SSRIs and SNRIs Fail

• Consider bupropion augmentation (add to existing antidepressant) or switch to bupropion monotherapy 150-300 mg SR. 2, 1

Critical Considerations

• Ensure adequate trial duration: A minimum of 4 weeks at licensed therapeutic dosage is required before determining treatment failure. 2

• Monitor for discontinuation syndrome: When switching from mirtazapine, taper appropriately to avoid withdrawal symptoms. 4

• Avoid subtherapeutic dosing: This is the most common reason for apparent treatment failure—ensure doses reach therapeutic levels (sertraline ≥100 mg, venlafaxine ≥75 mg). 2

• Mirtazapine's unique profile: While the patient failed mirtazapine, it has the fastest onset of action compared to all SSRIs with statistically significant earlier response, though response rates equalize after 4 weeks. 1, 5 This suggests the failure may have been related to tolerability rather than efficacy.

Why Not Other Options

• Not duloxetine initially: While duloxetine demonstrates equivalent efficacy to other antidepressants, it is particularly useful when comorbid pain is present, which is not mentioned in this case. 1

• Not continuing mirtazapine: The patient has already failed this medication, and there is no evidence supporting dose escalation after failure. 4

• Not trazodone: Patient has history of not tolerating this medication. 4