What to prescribe for anxiety when Selective Serotonin Reuptake Inhibitors (SSRIs) fail?

Treatment Options for Anxiety When SSRIs Fail

When SSRIs fail to adequately treat anxiety, serotonin-norepinephrine reuptake inhibitors (SNRIs) should be considered as the next line of treatment due to their dual mechanism of action targeting both serotonin and norepinephrine neurotransmitter systems. 1, 2

First-Line Alternative: SNRIs

• Venlafaxine is a well-established SNRI with demonstrated efficacy for anxiety disorders when SSRIs have failed, with effectiveness for various anxiety conditions including social anxiety disorder, generalized anxiety disorder, and panic disorder 3, 2
• Duloxetine is another SNRI option that can be considered, particularly in patients with comorbid pain conditions 4
• SNRIs work by inhibiting both serotonin and norepinephrine reuptake, providing a broader neurotransmitter effect that may benefit patients who did not respond to the more selective action of SSRIs 2

Venlafaxine Dosing and Administration:

• Start at a low dose (37.5-75mg/day) and gradually increase as tolerated 5
• Effective dose range is typically 75-225mg/day, with some patients requiring up to 375mg/day 5, 3
• Extended-release formulation allows for once-daily dosing and may have fewer side effects than immediate-release 3

Important Monitoring Considerations:

• Blood pressure monitoring is essential as venlafaxine can cause sustained hypertension, particularly at higher doses 5
• Discontinuation should always be gradual to prevent withdrawal symptoms, which can include dizziness, nausea, headache, irritability, sensory disturbances, and anxiety 5
• Weight and height should be monitored, especially in younger patients 5

Second-Line Alternatives

• Buspirone is a non-benzodiazepine anxiolytic that may be considered, particularly in older adults or when avoiding sexual side effects is a priority 4
• Mirtazapine, a noradrenergic and specific serotonergic antidepressant, may be beneficial especially when sleep disturbance is a prominent symptom 4, 2
• Pregabalin or gabapentin may be considered for specific anxiety disorders, particularly when other options have failed 4

Combination Therapy Approaches

• Cognitive-behavioral therapy (CBT) combined with medication shows superior outcomes compared to either treatment alone and should be strongly considered 1
• For treatment-resistant cases, augmentation strategies may include:
  • Adding an atypical antipsychotic in low doses (particularly for severe anxiety with paranoid features) 6
  • Combining an SNRI with buspirone 4

Cautions and Contraindications

• SNRIs should not be combined with MAOIs due to risk of serotonin syndrome 5
• Use SNRIs cautiously in patients with:
  • Cardiovascular disease or hypertension 5
  • Seizure disorders 1
  • Hepatic impairment (particularly duloxetine) 1
• Monitor for emergence of suicidal ideation, especially in younger patients and during the initial treatment period or dose changes 5
• Discontinuation syndrome is common with SNRIs and requires slow tapering when stopping treatment 5

Special Populations

• For elderly patients, start with lower doses and titrate more slowly; sertraline or escitalopram may be preferred first, followed by SNRIs if needed 4
• For patients with comorbid PTSD, venlafaxine has shown efficacy as a second-line option after SSRIs 6
• For patients with OCD who failed SSRI treatment, venlafaxine has shown promising results in open-label studies 7

Common Pitfalls to Avoid

• Avoid abrupt discontinuation of SNRIs, which can lead to withdrawal symptoms including dizziness, sensory disturbances, anxiety, and irritability 5
• Avoid combining multiple serotonergic medications without careful monitoring due to risk of serotonin syndrome 1, 5
• Don't overlook the importance of psychotherapy; medication alone may not provide optimal outcomes 1
• Benzodiazepines should generally be avoided or used only short-term due to risk of dependence and potential to worsen anxiety long-term 6, 4

Remember that treatment response may take 4-6 weeks to become fully evident, and an adequate trial should be given before concluding that a medication is ineffective 1, 2.