What are second-line treatments, including antipsychotics, for anxiety when Selective Serotonin Reuptake Inhibitors (SSRIs) and Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs) are not effective?

Second-Line Treatments for Anxiety When SSRIs and SNRIs Fail

For patients with anxiety who have not responded to SSRIs and SNRIs, benzodiazepines, pregabalin, gabapentin, and cognitive behavioral therapy are recommended as second-line treatments, with benzodiazepines providing the fastest relief. 1

Pharmacological Second-Line Options

Fast-Acting Options

• Benzodiazepines (alprazolam, bromazepam, clonazepam) provide rapid anxiety relief and are recommended as second-line agents by the Canadian Clinical Practice Guidelines 1
  • Act within 30-60 minutes of administration
  • Should be used cautiously due to risk of dependence and potential worsening of symptoms with long-term use 2
  • Most appropriate for short-term use or acute anxiety episodes

Anticonvulsants

• Pregabalin has demonstrated efficacy as a second-line treatment for anxiety disorders 1, 3
  • Onset of action is typically within days (faster than SSRIs/SNRIs)
  • Particularly useful for patients with comorbid neuropathic pain
• Gabapentin is recommended as a second-line option by Canadian guidelines 1, 3
  • May be particularly helpful for patients with comorbid pain conditions
  • Generally well-tolerated with fewer dependence concerns than benzodiazepines

Antipsychotics

• Quetiapine has shown mixed results in anxiety disorders 1, 4
  • The Canadian CPG notes negative evidence for quetiapine in social anxiety disorder 1
  • However, some evidence supports its use in treatment-resistant generalized anxiety disorder 4, 5
  • Consider for patients with prominent sleep disturbances or comorbid mood symptoms
• Risperidone and aripiprazole have shown some efficacy as augmentation strategies 2, 4
  • More evidence exists for their use in obsessive-compulsive disorder and PTSD than in other anxiety disorders
  • Should be monitored carefully for metabolic side effects

Other Pharmacological Options

• Buspirone (azapirone class) has shown efficacy in open-label studies 2, 3
  • Non-sedating and non-addictive alternative
  • Takes 2-3 weeks for full effect (not fast-acting)
• Mirtazapine may be beneficial due to its anxiolytic and sleep-promoting properties 3
  • Can help with comorbid insomnia and depression
  • Onset of action may be faster than SSRIs (1-2 weeks)

Non-Pharmacological Options

• Cognitive Behavioral Therapy (CBT) is strongly recommended for anxiety disorders 1
  • Structured approach with approximately 14 individual sessions over 4 months
  • Individual therapy is preferred over group therapy due to superior clinical effectiveness 1
  • Self-help CBT with professional support is an alternative for patients who decline face-to-face therapy 1

Treatment Algorithm

1. First step: Try a different SSRI or SNRI if only one has been tried
2. For rapid relief: Consider short-term benzodiazepine (alprazolam, clonazepam) while initiating other treatments 1, 3
3. Second-line options:
   • Pregabalin or gabapentin (especially with comorbid pain) 1, 3
   • Buspirone (for generalized anxiety) 3
   • Low-dose antipsychotic (quetiapine, risperidone) for severe cases 4, 5
4. Concurrent treatment: Implement CBT regardless of medication choice 1

Important Considerations and Caveats

• Benzodiazepines should be used with caution due to risk of dependence, tolerance, and potential worsening of anxiety with long-term use 2
• Antipsychotics require careful monitoring for metabolic side effects, weight gain, and extrapyramidal symptoms 4
• Treatment resistance should prompt reassessment of diagnosis and evaluation for comorbid conditions that may complicate treatment 4
• Combination therapy (medication plus CBT) often yields better results than either approach alone 1
• Regular monitoring by a physician with expertise in anxiety disorders is essential for evaluating treatment response 1