What are the off-label medications used in the treatment of anxiety disorders and their dosing?

Off-Label Medications for Anxiety Disorders

The most commonly used off-label medications for anxiety disorders include benzodiazepines (alprazolam, clonazepam, bromazepam), pregabalin, gabapentin, and quetiapine, with benzodiazepines and pregabalin having the strongest evidence as second-line agents when SSRIs/SNRIs fail. 1

Benzodiazepines (Second-Line, Off-Label for Most Anxiety Disorders)

The Canadian Clinical Practice Guidelines recommend benzodiazepines as second-line agents for rapid anxiety relief when first-line treatments fail 1. However, they are not recommended for routine first-line use due to dependence potential 2.

Common benzodiazepines and typical dosing:

• Alprazolam: 0.25-0.5 mg 2-3 times daily, titrate up to 1-4 mg/day in divided doses 1
• Clonazepam: 0.25-0.5 mg twice daily, titrate up to 1-4 mg/day in divided doses 1
• Bromazepam: 3-6 mg 2-3 times daily, up to 18 mg/day 1

Key caveat: While effective for rapid symptom control, benzodiazepines carry risks of dependence, withdrawal, cognitive impairment, and should be used short-term or intermittently rather than as chronic monotherapy 2, 3.

Anticonvulsants/GABA Modulators

Pregabalin (Second-Line)

Pregabalin has demonstrated efficacy as a second-line treatment for anxiety disorders according to Canadian guidelines 1.

Dosing:

• Start: 150 mg/day in 2-3 divided doses
• Target: 300-600 mg/day in 2-3 divided doses
• Maximum: 600 mg/day 4, 3

Gabapentin (Second-Line)

Gabapentin is recommended as a second-line option, particularly for patients with comorbid pain conditions 1.

Dosing:

• Start: 300 mg once daily or 300 mg three times daily
• Target: 900-3600 mg/day in 3 divided doses
• Typical effective range: 1200-3600 mg/day 4, 3

Atypical Antipsychotics (Limited Evidence)

Quetiapine

Quetiapine has the most evidence among antipsychotics, specifically for generalized anxiety disorder (GAD), though evidence quality is limited 5.

Dosing for GAD:

• Start: 25-50 mg at bedtime
• Target: 50-300 mg/day (typically 150-300 mg)
• Extended-release formulation: 50-300 mg once daily 4, 6

Important caveat: The Canadian Clinical Practice Guidelines note negative evidence for quetiapine in social anxiety disorder 1. A 2024 umbrella review found insufficient high-quality evidence for antipsychotics in anxiety disorders outside of quetiapine in GAD, and risks/side effects may outweigh efficacy 5. Metabolic side effects (weight gain, diabetes, dyslipidemia) are significant concerns 5.

Other Antipsychotics

First-generation antipsychotics (except trifluoperazine, which has FDA approval) and other second-generation antipsychotics lack sufficient evidence and are not recommended 5, 4.

Beta-Blockers

Propranolol (Performance Anxiety/Specific Situations)

While not extensively studied for chronic anxiety disorders, propranolol is used off-label for performance anxiety and situational anxiety 4, 3.

Dosing:

• Performance anxiety: 10-40 mg taken 30-60 minutes before the anxiety-provoking event
• Chronic use (if needed): 20-40 mg 2-3 times daily, up to 120-240 mg/day 4

Note: Beta-blockers have limited evidence for generalized anxiety treatment and are primarily useful for physical symptoms of anxiety in specific situations 7, 4.

Tricyclic Antidepressants (Off-Label)

Clomipramine

While clomipramine has strong evidence for OCD, it can be used off-label for anxiety disorders 7.

Dosing:

• Start: 25 mg at bedtime
• Titrate: Increase by 25 mg every 3-7 days
• Target: 100-250 mg/day
• Maximum: 250 mg/day 7, 3

Caveat: Clomipramine has a less favorable side effect profile compared to SSRIs (anticholinergic effects, cardiac conduction effects, weight gain), limiting its use as a first-line agent 7.

Azapirones

Buspirone

Buspirone is used off-label for various anxiety disorders, though it has FDA approval for GAD 4, 3, 6.

Dosing:

• Start: 7.5 mg twice daily
• Titrate: Increase by 5 mg every 2-3 days
• Target: 15-30 mg/day in 2-3 divided doses
• Maximum: 60 mg/day 3, 6

Key limitation: Buspirone has a delayed onset of action (2-4 weeks) and may be less effective in patients previously treated with benzodiazepines 3, 6.

Antihistamines

Hydroxyzine

Hydroxyzine is used off-label for short-term anxiety relief 4, 3.

Dosing:

• 25-100 mg 3-4 times daily as needed
• Maximum: 400 mg/day 4

Note: Sedation and anticholinergic effects limit long-term use 4.

Mixed Antidepressants (Off-Label)

Mirtazapine

Mirtazapine can be used off-label for anxiety disorders 4, 3.

Dosing:

• Start: 7.5-15 mg at bedtime
• Target: 15-45 mg at bedtime
• Typical effective dose: 30 mg/day 4, 3

Consideration: Sedation and weight gain are common side effects that may limit tolerability 4.

Treatment Algorithm Approach

When SSRIs/SNRIs fail or are not tolerated:

1. First consideration: Add or switch to pregabalin (300-600 mg/day) or gabapentin (1200-3600 mg/day), especially if comorbid pain exists 1

2. For rapid relief needed: Short-term benzodiazepine (clonazepam 0.5-2 mg/day or alprazolam 1-4 mg/day) while titrating other agents 1

3. For GAD specifically: Consider quetiapine 150-300 mg/day if other options fail, weighing metabolic risks 1, 5

4. Avoid: Routine use of antipsychotics outside of quetiapine for GAD due to insufficient evidence and unfavorable risk-benefit ratio 5

5. Always combine with CBT: Combination therapy yields superior outcomes to medication alone 1, 2

Common Pitfalls

• Benzodiazepine dependence: Limit duration and use lowest effective dose; avoid in patients with substance use history 2, 3
• Antipsychotic overuse: Most antipsychotics lack evidence in anxiety disorders and carry significant metabolic risks 5
• Inadequate trial duration: Off-label agents may require 8-12 weeks for full effect, similar to SSRIs 7, 3
• Polypharmacy without rationale: Ensure adequate trials of first-line agents before adding off-label medications 1, 2