What is the next treatment option for a patient with depression and anxiety who has not responded to Selective Serotonin Reuptake Inhibitors (SSRIs) and bupropion?

Treatment-Resistant Depression with Comorbid Anxiety

Primary Recommendation

For patients with depression and anxiety who have failed SSRIs and bupropion, switch to venlafaxine (SNRI) at therapeutic doses (75-225 mg daily) or consider augmentation with mirtazapine, as these agents demonstrate superior efficacy for treating comorbid anxiety symptoms compared to other second-generation antidepressants. 1, 2

Treatment Algorithm

Step 1: Optimize Current Regimen or Switch to Venlafaxine

• Venlafaxine demonstrates superior efficacy compared to fluoxetine specifically for treating anxiety symptoms in patients with comorbid depression and anxiety, making it the preferred next-line agent after SSRI and bupropion failure 3, 2
• Start venlafaxine ER at 75 mg daily and titrate to 150-225 mg daily over 2-4 weeks 2
• An adequate trial requires maintaining therapeutic dosing for at least 4-6 weeks before determining treatment failure 1, 2
• Evidence from head-to-head trials shows venlafaxine had statistically significantly better response and remission rates than fluoxetine in patients with major depression and anxiety symptoms 3

Step 2: Consider Mirtazapine for Rapid Symptom Relief

• Mirtazapine provides statistically significantly faster onset of action compared to SSRIs and is particularly beneficial for patients with comorbid anxiety and insomnia due to its sedating properties 1
• Dose mirtazapine 15-45 mg at bedtime, with most patients responding to 30 mg daily 1
• This option is especially valuable if the patient has prominent insomnia or requires rapid symptom relief 1

Step 3: Augmentation Strategies if Monotherapy Fails

If venlafaxine or mirtazapine monotherapy produces partial response after 6-8 weeks, consider augmentation rather than switching: 3, 1

• Add atypical antipsychotics (aripiprazole 2-15 mg or quetiapine 50-300 mg) for partial responders, as recommended by the National Institute of Mental Health 1, 2
• Lithium augmentation is one of the best-documented treatments for treatment-resistant depression, though it requires careful monitoring of blood levels, thyroid function, and renal function 1, 2
• Combination venlafaxine plus bupropion has demonstrated synergistic effects in treatment-resistant depression, significantly reducing depressive symptoms and increasing social function 4

Step 4: Alternative Augmentation Options

• Bupropion augmentation (if not already tried as monotherapy) decreases depression severity more than buspirone augmentation, with lower discontinuation rates due to adverse events 1, 2
• Consider switching to a different SSRI (such as sertraline 100-200 mg daily) if venlafaxine is not tolerated, as the STAR*D trial showed that 1 in 4 patients became symptom-free when switching between antidepressants 2

Critical Evidence Considerations

Comparative Efficacy Data

• SSRIs show a modest advantage over bupropion in anxious depression (6% difference in response rates, NNT=17), providing theoretical support for serotonin's central role in regulating anxiety symptoms 5
• Among patients with anxious depression, SSRI response rates were 65.4% versus 59.4% for bupropion (p=0.03) 5
• In adolescents with SSRI-resistant depression, a second trial of an SSRI produced greater and faster improvement compared to venlafaxine when cognitive behavioral therapy was not provided 6
• However, when combined with CBT, SSRIs and venlafaxine produced similar improvements 6

Safety Considerations

• Monitor for serotonin syndrome when combining multiple serotonergic agents, particularly when adding bupropion to SSRIs or SNRIs, as bupropion inhibits cytochrome P450 2D6 and can increase SSRI blood levels 7
• Early manifestations of serotonin syndrome (myoclonic jerks, confusion, agitation) can be misinterpreted as worsening depression 7
• Venlafaxine and mirtazapine are generally well-tolerated with safety profiles comparable to SSRIs 8

Common Pitfalls to Avoid

• Do not declare treatment failure before completing an adequate trial: minimum 4 weeks at therapeutic (not subtherapeutic) doses 1, 2
• Avoid using subtherapeutic doses: venlafaxine 37.5 mg is inadequate for treating either depression or anxiety; therapeutic range is 75-225 mg daily 2
• Do not add multiple serotonergic agents simultaneously without careful monitoring for serotonin syndrome 7
• Reassess within 6-8 weeks of initiating or modifying treatment, as recommended by the American College of Physicians 3

When to Consider Non-Pharmacological Options

• If multiple augmentation strategies fail after adequate trials, consider cognitive behavioral therapy or electroconvulsive therapy 1
• For severe, treatment-refractory cases, intensive outpatient or residential treatment programs may be necessary 3