What is the best course of action for a patient with increased symptoms who has been on buspirone (an anxiolytic medication) for years and has previously tried several selective serotonin reuptake inhibitors (SSRIs) with no improvement?

Treatment-Refractory Anxiety: Next Steps After Failed Buspirone and SSRIs

Discontinue buspirone and initiate a tricyclic antidepressant (TCA) at low doses (e.g., amitriptyline 10 mg or nortriptyline 10-25 mg at bedtime), titrating slowly to 30-50 mg daily while monitoring for side effects, as TCAs are effective second-line agents for anxiety disorders with strong evidence for treatment-resistant cases. 1

Rationale for Discontinuing Buspirone

• Buspirone has demonstrated weak efficacy in treatment-refractory cases, particularly when symptoms are worsening despite years of use 2
• Research specifically examining buspirone augmentation of SSRIs in refractory depression showed minimal improvement, with only 2 of 10 patients achieving partial remission and no complete recoveries 2
• Long-term buspirone therapy (up to one year) is safe but not generally recommended for chronic anxiety, and the need for continued therapy should be periodically reevaluated 3
• Buspirone's mechanism as a partial 5-HT1A agonist may be insufficient for severe or treatment-resistant anxiety 4

First-Line Alternative: Tricyclic Antidepressants

TCAs represent the strongest evidence-based second-line treatment for anxiety disorders after SSRI failure:

Efficacy Evidence

• TCAs demonstrate strong efficacy for global symptom relief and abdominal pain in anxiety-related conditions (RR 0.67,95% CI 0.54-0.82 for global symptoms) 1
• The British Society of Gastroenterology guidelines provide a strong recommendation (moderate quality evidence) for TCAs as second-line gut-brain neuromodulators 1
• TCAs work independently of effects on depression and may take several weeks to show benefit 1

Specific Dosing Strategy

• Start with amitriptyline 10 mg once daily at bedtime (proven effective even at this low dose) 1
• Titrate slowly to maximum 30-50 mg once daily at 1-2 week intervals as tolerated 1
• For patients with constipation concerns, consider secondary amine TCAs (desipramine or nortriptyline) due to lower anticholinergic effects 1

Patient Education Requirements

• Careful explanation of rationale is essential, as patients may be concerned about "antidepressant" use for anxiety 1
• Counsel about side effect profile: dry mouth, sedation, constipation are common but often manageable with dose titration 1
• Close monitoring is required, particularly during initiation and dose adjustments 1

Alternative Second-Line Options

SNRIs (Serotonin-Norepinephrine Reuptake Inhibitors)

• Consider switching to an SNRI (venlafaxine, duloxetine) if TCAs are not tolerated 1
• SNRIs may be effective when SSRIs have failed, as they provide dual mechanism of action 1
• Requires similar careful explanation and monitoring as TCAs 1

Combination Therapy Consideration

• If the patient is adolescent (6-18 years), combination CBT plus medication is superior to either alone for social anxiety, generalized anxiety, separation anxiety, or panic disorder 1
• The Child-Adolescent Anxiety Multimodal Study (CAMS) demonstrated that combination treatment improved primary anxiety, global function, response rates, and remission compared to monotherapy 1

Critical Safety Considerations

Avoid Dangerous Combinations

• Never combine buspirone with MAOIs due to risk of elevated blood pressure and serotonin syndrome 5
• At least 14 days must elapse between discontinuing buspirone and starting an MAOI, or vice versa 5
• Monitor for serotonin syndrome when combining any serotonergic agents: mental status changes, neuromuscular hyperactivity (tremor, rigidity, myoclonus), autonomic instability (tachycardia, hypertension, diaphoresis) 1, 5

TCA-Specific Warnings

• TCAs have higher withdrawal rates due to adverse effects compared to placebo (RR 2.11,95% CI 1.35-3.28) 1
• Anticholinergic effects (dry mouth, constipation, urinary retention) and cardiovascular effects require monitoring 1
• TCAs are more dangerous in overdose than SSRIs, requiring careful assessment of suicide risk 1

What NOT to Do

SSRIs Are Not Recommended

• The AGA suggests against using SSRIs in treatment-refractory cases (conditional recommendation, low certainty) 1
• Multiple SSRI trials have already failed in this patient, and evidence shows SSRIs have inconsistent efficacy with possible worsening of symptoms (RR 0.74,95% CI 0.52-1.06, with upper boundary suggesting harm) 1

Buspirone Augmentation Is Ineffective

• Do not continue buspirone or attempt augmentation strategies given the weak evidence for efficacy in refractory cases 2
• The theoretical benefit of buspirone augmentation under "poop-out" states (serotonin depletion) lacks robust clinical evidence 6

Monitoring and Follow-Up

• Reassess at 2-4 weeks after TCA initiation for tolerability and early response 1
• Full therapeutic trial requires 6-8 weeks at target dose before determining efficacy 1
• If inadequate response to TCA, consider switching to a different TCA, adding CBT if not already implemented, or referring to specialty care for consideration of atypical antipsychotics, glutamate modulators, or neuromodulation 1
• Continue successful treatment for 4-9 months after satisfactory response; longer duration may be beneficial for recurrent cases 1