What is the next best step for a patient with treatment-resistant depression and anxiety who has failed multiple Selective Serotonin Reuptake Inhibitors (SSRIs) and Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs) and is currently not responding to Viibryd (vilazodone)?

Treatment-Resistant Depression and Anxiety: Next Steps After Viibryd Failure

For a patient who has failed multiple SSRIs, SNRIs, and vilazodone (Viibryd), the most evidence-based next step is to switch to either bupropion sustained-release, mirtazapine, or consider augmentation with an atypical antipsychotic such as aripiprazole, brexpiprazole, or quetiapine extended-release. 1, 2

Algorithmic Approach to Treatment Selection

Step 1: Switch to a Different Mechanism Antidepressant

Since this patient has failed multiple serotonergic agents (SSRIs, SNRIs, and vilazodone which is an SSRI with 5-HT1A partial agonist activity), switching to an antidepressant with a different mechanism is the logical next step:

Bupropion (sustained-release or extended-release):

• This should be your first consideration as it is the only antidepressant with no serotonergic activity, working instead on norepinephrine and dopamine 3
• The STAR*D trial showed that switching to bupropion sustained-release achieved symptom-free status in 1 in 4 patients after initial treatment failure, with no difference compared to other switching strategies 1
• Maximum dose: 400 mg/day for sustained-release formulation 3
• Onset of action: 2 weeks, with full efficacy at 4 weeks 3
• Key advantage: No sexual side effects and may help with comorbid smoking cessation 3
• Critical caveat: Contraindicated if seizure history; must titrate gradually to avoid seizure risk 3

Mirtazapine:

• Consider this as an alternative first switch option, especially if the patient has prominent insomnia or poor appetite 1
• Unique mechanism: blocks alpha-2 presynaptic receptors, enhancing norepinephrine and serotonin release 3
• Shows significantly faster onset of action (1-2 weeks) compared to SSRIs 1, 3
• Dose range: 15-45 mg once daily at bedtime 3
• Key advantage: Particularly helpful for anxiety with insomnia and can improve appetite 3
• Critical caveat: Sedation and weight gain are common; may be beneficial or problematic depending on patient presentation 3

Step 2: If Switching Fails, Consider Augmentation with Atypical Antipsychotics

Atypical antipsychotics are the most widely studied and FDA-approved augmentation strategy for treatment-resistant depression 2:

FDA-approved options for augmentation:

• Aripiprazole (most evidence, generally well-tolerated) 2
• Brexpiprazole (newer, similar profile to aripiprazole) 2
• Quetiapine extended-release (also effective for anxiety symptoms) 2, 4
• Cariprazine 2
• Olanzapine-fluoxetine combination (though patient has already failed SSRIs) 2

Quetiapine deserves special consideration for this patient with comorbid anxiety:

• Most evidence for GAD among atypical antipsychotics 4
• Approximately 50% of patients tolerate side effects (mainly sedation and fatigue), and among those who continue, significant anxiety reduction occurs 4
• Can be used as monotherapy or augmentation 4

Critical caveats for atypical antipsychotics:

• Must weigh benefits against risks: weight gain, metabolic syndrome, akathisia, and tardive dyskinesia 2
• Requires metabolic monitoring (weight, glucose, lipids) 2
• Generally reserved for more severe or refractory cases 2

Step 3: Strongly Consider Adding Cognitive Behavioral Therapy

CBT should be integrated at this stage if not already implemented:

• For anxiety disorders, structured CBT (14 sessions over 4 months, 60-90 minutes each) is as effective as pharmacotherapy 1
• For depression with anxiety, combining CBT with medication may improve outcomes beyond medication alone 1
• Internet-delivered or self-help CBT with support is an option if face-to-face therapy is unavailable 1

What NOT to Do

Avoid switching to another SSRI or SNRI at this point:

• The patient has already failed multiple agents in these classes 1
• The STAR*D trial showed no superiority among SSRIs/SNRIs when switching after initial failure 1

Avoid benzodiazepines for long-term anxiety management:

• May worsen depression and have addiction potential 5
• Should only be used short-term if at all 5

Do not use gabapentin or topiramate:

• Controlled studies in adults have not found these effective for depression 1

Practical Implementation

Recommended sequence:

1. First attempt: Switch to bupropion SR 150 mg daily, titrate to 300-400 mg/day over 3-4 weeks 3
2. If insomnia/poor appetite prominent: Switch to mirtazapine 15 mg at bedtime, increase to 30-45 mg as tolerated 3
3. If switching fails after 6-8 weeks: Add augmentation with aripiprazole (start 2-5 mg daily) or quetiapine XR (start 50 mg, titrate to 150-300 mg) 2, 4
4. Throughout: Integrate structured CBT for both depression and anxiety 1

Timeline expectations:

• Allow 4-6 weeks at therapeutic doses before declaring treatment failure 3
• Some improvement should be seen within 1-2 weeks if medication will be effective 3