What alternative pharmacologic and non‑pharmacologic treatments are appropriate for an adult with generalized anxiety disorder who declines a selective serotonin reuptake inhibitor (SSRI)?

Alternative Treatments for Generalized Anxiety Disorder When SSRI is Declined

When a patient with generalized anxiety disorder declines SSRI therapy, offer cognitive behavioral therapy (CBT) as first-line monotherapy, or alternatively prescribe an SNRI (venlafaxine XR 75-225 mg/day or duloxetine 60-120 mg/day) as the primary pharmacologic option. 1

First-Line Non-Pharmacologic Treatment

Cognitive behavioral therapy should be your immediate recommendation when SSRIs are declined. 1

• Individual CBT demonstrates large effect sizes for GAD (Hedges g = 1.01) and is prioritized over group therapy due to superior clinical and cost-effectiveness 1
• Structure treatment as 12-20 sessions to achieve significant symptomatic and functional improvement 2
• CBT includes specific elements: education on anxiety, cognitive restructuring to challenge distortions, relaxation techniques, and gradual exposure when appropriate 1
• Response rates to CBT range from 47-75% in published studies, comparable to pharmacotherapy 3

First-Line Pharmacologic Alternatives

If the patient requires or prefers medication but refuses SSRIs, prescribe an SNRI as your first pharmacologic choice. 1

SNRIs (Serotonin-Norepinephrine Reuptake Inhibitors)

• Venlafaxine extended-release 75-225 mg/day demonstrates efficacy for GAD with an NNT of 4.94 4, 5
• Start at 75 mg daily and titrate based on response, monitoring blood pressure for sustained hypertension 1
• Duloxetine 60-120 mg/day is equally effective and has additional benefits for patients with comorbid pain conditions 1
• Begin duloxetine at 30 mg daily for one week to reduce nausea, then increase to 60 mg 1
• SNRIs may have greater effect on both anxiety and depression symptoms due to dual action on serotonin and norepinephrine reuptake 2

Second-Line Pharmacologic Options

If SNRIs are also declined or contraindicated, consider pregabalin or buspirone as second-line agents. 1, 5

Pregabalin/Gabapentin

• Pregabalin shows efficacy in GAD, particularly for patients with comorbid pain conditions 1
• This calcium-channel modulator represents a mechanistically distinct option from antidepressants 3

Buspirone

• Buspirone 20 mg three times daily (titrated from 5 mg twice daily over 2-4 weeks) may be effective 2
• Evidence across trials is inconsistent, with some studies showing benefit while others do not 3
• Buspirone has higher discontinuation rates (20.6%) compared to other augmentation strategies 2

Medications to Avoid

Do not prescribe benzodiazepines for long-term GAD treatment despite their short-term efficacy. 1, 3, 5

• Benzodiazepines carry risks of dependence, tolerance, withdrawal, and cognitive impairment 1
• Reserve benzodiazepines only for short-term use if absolutely necessary 3

Avoid tricyclic antidepressants due to unfavorable risk-benefit profile, particularly cardiac toxicity. 1

Combination Therapy Strategy

Combining CBT with any pharmacologic treatment provides superior outcomes compared to either modality alone. 2, 1

• Combination therapy (CBT + medication) demonstrates better efficacy than monotherapy for moderate to severe GAD 2, 6
• One pilot study showed that adding modular CBT to escitalopram resulted in full remission for most patients, with some maintaining response after medication discontinuation 6
• This synergistic approach addresses both neurobiological and psychological components simultaneously 2

Adjunctive Non-Pharmacologic Interventions

Recommend structured physical activity and lifestyle modifications as adjuncts to primary treatment. 1

• Regular cardiovascular exercise provides moderate to large reduction in anxiety symptoms 1
• Breathing techniques, progressive muscle relaxation, grounding strategies, and mindfulness are useful adjunctive strategies 1
• Avoid excessive caffeine and alcohol as both exacerbate anxiety symptoms 4
• Address sleep hygiene, as insomnia commonly co-occurs with anxiety 4

Monitoring and Treatment Duration

Assess treatment response every 2-4 weeks using standardized anxiety rating scales (GAD-7 or HAM-A). 2, 1

• Allow 8-12 weeks at therapeutic doses before declaring treatment failure 2, 1
• Continue effective medication for a minimum of 9-12 months after achieving remission to prevent relapse 1
• Modify treatment strategy if no improvement occurs after 8 weeks at therapeutic doses despite good adherence 1

Critical Pitfalls to Avoid

• Do not commence pharmacotherapy before trialing evidence-based CBT, which provides more durable benefits 1
• Do not continue ineffective treatment beyond 8 weeks, as this delays recovery and worsens outcomes 2
• Do not overlook functional impairment assessment, as significant impairment may justify treatment even with mild symptom scores 1
• Patients with anxiety commonly avoid follow-through on referrals, so proactively assess and address barriers to treatment adherence 1