What should I prescribe for a patient with severe anxiety who has tried every Selective Serotonin Reuptake Inhibitor (SSRI) and Serotonin-Norepinephrine Reuptake Inhibitor (SNRI)?

Treatment Options for Severe Anxiety After SSRI/SNRI Failure

For patients with severe anxiety who have failed all SSRIs and SNRIs, consider pregabalin or gabapentin as second-line agents, with benzodiazepines (specifically clonazepam or alprazolam) reserved for short-term use or as adjunctive therapy, while simultaneously implementing cognitive behavioral therapy (CBT) which should be prioritized as it has comparable or superior efficacy to pharmacotherapy alone. 1

Second-Line Pharmacological Options

Pregabalin/Gabapentin (Preferred Second-Line)

• Pregabalin and gabapentin are recommended as second-line agents when first-line SSRIs/SNRIs are ineffective or not tolerated 1
• These medications have demonstrated efficacy in generalized anxiety disorder and offer particular benefit for patients with comorbid pain conditions 1
• The Canadian Clinical Practice Guideline lists pregabalin as a first-line option alongside SSRIs/SNRIs, and gabapentin as a second-line agent 2

Benzodiazepines (Use with Caution)

• Benzodiazepines show superior tolerability and rapid onset of action compared to antidepressants, but carry risks of tolerance and dependence 3, 4
• The Canadian guideline recommends alprazolam, bromazepam, and clonazepam as second-line options 2
• Clonazepam and alprazolam demonstrate the strongest evidence for efficacy, ranking highest for response rates and dropout tolerability in network meta-analysis 4
• Diazepam also shows strong efficacy and was ranked among the most effective and tolerable medications 4

Benzodiazepine Dosing (from FDA labeling):

• Clonazepam for panic disorder: Start 0.25 mg twice daily, increase to target dose of 1 mg/day after 3 days, with maximum of 4 mg/day if needed 5
• Increases should be made in 0.125-0.25 mg increments every 3 days 5
• Consider single bedtime dosing to reduce daytime somnolence 5

Critical Considerations for Benzodiazepine Use

Common Pitfall: Benzodiazepines are often avoided entirely due to dependence concerns, but they represent the most effective class for treatment-resistant anxiety in terms of both efficacy and tolerability 4

• Benzodiazepines were the only medication class associated with lower dropout rates than placebo and ranked first for tolerability 4
• They show significantly lower dropout rates compared to SSRIs, SNRIs, and TCAs 4
• The rapid onset of action (unlike the several-week delay with SSRIs) addresses the immediate suffering in severe anxiety 3
• Long-term use requires careful monitoring for tolerance and dependence 3

Cognitive Behavioral Therapy (Essential Component)

CBT should be implemented regardless of medication choice, as it provides comparable or superior outcomes to pharmacotherapy alone 1

• Individual CBT is prioritized over group therapy due to superior clinical and cost-effectiveness 2, 1
• Structure: 12-20 sessions over approximately 3-4 months, with 60-90 minute individual sessions 2, 1
• CBT elements should include: education on anxiety, cognitive restructuring, relaxation techniques, and gradual exposure 1
• Large effect size for generalized anxiety disorder (Hedges g = 1.01) 1

Alternative Strategies to Consider

Switching Within Antidepressant Classes

• Although the patient has "tried every SSRI and SNRI," ensure adequate trials were conducted: at least 8-12 weeks at therapeutic doses 1
• Consider that individual responses vary; some patients respond to one SSRI after failing another 1

Medications with Limited Evidence

• Vortioxetine has one positive RCT for social anxiety disorder but lacks meta-analytic data 2
• Antipsychotics (quetiapine, olanzapine, risperidone) have shown mixed results as adjunctive therapy, with most trials being underpowered 6
• The Canadian guideline specifically deprecates quetiapine for social anxiety based on negative evidence 2

Treatment Algorithm

1. First: Verify adequate SSRI/SNRI trials (8-12 weeks at therapeutic doses) 1

2. Second: Initiate pregabalin or gabapentin as the preferred second-line pharmacological option 1

3. Third: If inadequate response, consider adding or switching to a benzodiazepine (clonazepam or alprazolam preferred based on evidence) 4

   • Start clonazepam 0.25 mg twice daily, titrate to 1 mg/day 5
   • Monitor for tolerance and dependence with long-term use 3

4. Concurrent: Implement structured individual CBT (12-20 sessions) regardless of medication choice 1

5. Monitor response using standardized anxiety rating scales (e.g., HAM-A) 1

Important Caveats

• The evidence base for treatment-resistant anxiety disorders is limited, with few high-quality RCTs comparing options after SSRI/SNRI failure 2, 6
• Most studies focus on first-line treatments; research on inadequate responders is lacking 2
• The quality of benzodiazepine studies is generally lower than SSRI studies, though the efficacy signal remains strong 4
• Avoid beta-blockers (atenolol, propranolol) as they have negative evidence for anxiety disorders 2