What is the typical medication regimen for treating generalized anxiety disorder, including first‑line SSRIs or SNRIs, dosing, and adjunct non‑pharmacologic therapies?

Typical Medication Regimen for Generalized Anxiety Disorder

Start with escitalopram 10 mg once daily or sertraline 50 mg once daily as first-line pharmacotherapy, combined with individual cognitive behavioral therapy (CBT) for optimal outcomes. 1, 2

First-Line Pharmacological Treatment

Preferred SSRIs

• Escitalopram and sertraline are the top-tier first-line agents due to their established efficacy, favorable side effect profiles, and lower risk of discontinuation symptoms compared to other SSRIs. 1
• Escitalopram should be initiated at 10 mg once daily (morning or evening, with or without food), with potential increase to 20 mg after a minimum of one week if needed. 2
• Sertraline should be started at 50 mg once daily (or 25 mg daily for the first week in highly anxious patients to minimize initial activation), then titrated in 50 mg increments every 1-2 weeks up to a maximum of 200 mg daily. 1, 3

Alternative First-Line SSRIs

• Paroxetine and fluvoxamine are equally effective but reserved as second-tier options due to higher rates of discontinuation symptoms and greater potential for drug-drug interactions. 4, 1
• Paroxetine is FDA-approved for GAD and can be started at 20 mg daily, titrated to 40-60 mg/day, though it carries higher discontinuation syndrome risk. 1, 3

First-Line SNRIs

• Venlafaxine extended-release (75-225 mg/day) is an effective alternative when SSRIs are inadequate, ineffective, or not tolerated after 8-12 weeks at therapeutic doses. 4, 1
• Duloxetine (60-120 mg/day) has demonstrated efficacy in GAD and offers additional benefits for patients with comorbid pain conditions. 1, 5
• Duloxetine should be initiated at 30 mg once daily for 1 week to allow adjustment, then increased to 60 mg once daily; doses greater than 60 mg/day show no evidence of additional benefit. 5

Expected Timeline and Response Rates

• Statistically significant improvement begins by week 2, with clinically significant improvement expected by week 6, and maximal therapeutic benefit achieved by week 12 or later. 1
• Allow 6-8 weeks for an adequate trial at therapeutic doses before considering the medication ineffective. 1, 6
• Approximately 38% of patients do not achieve treatment response during 6-12 weeks, and 54% do not achieve remission, necessitating treatment adjustments. 1, 3

Essential Non-Pharmacological Component

• Individual CBT specifically designed for GAD (12-20 sessions over 3-4 months) should be offered alongside medication, as combination treatment yields superior outcomes compared to either modality alone. 4, 1
• Individual CBT is prioritized over group therapy due to superior clinical and cost-effectiveness. 4
• If face-to-face CBT is unavailable or declined, self-help CBT with professional support is a viable alternative. 4

Second-Line Pharmacological Options

• Pregabalin can be considered when first-line SSRIs/SNRIs are ineffective or not tolerated, particularly for patients with comorbid pain conditions. 1, 7
• Benzodiazepines (alprazolam, bromazepam, clonazepam) are recommended only for short-term adjunctive use (days to a few weeks) due to high risk of dependence, tolerance, cognitive impairment, and withdrawal syndromes—never as first-line or long-term therapy. 4, 1, 7

Treatment Duration and Maintenance

• Continue effective medication for a minimum of 9-12 months after achieving remission to prevent relapse. 1, 6, 7
• For patients with recurrent episodes or chronic symptoms, consider longer duration (≥1 year) or indefinite maintenance therapy. 1, 6
• Reassess monthly until symptoms stabilize, then every 3 months using standardized scales (GAD-7 or HAM-A). 1

Monitoring Requirements

• Monitor for treatment-emergent suicidality closely during the first 1-2 weeks after initiation or dose changes, especially in patients under age 24 (pooled risk 1% vs. 0.2% placebo, NNH=143). 1, 3
• Assess for common SSRI/SNRI side effects: nausea, sexual dysfunction, headache, insomnia, dry mouth, diarrhea, dizziness, and somnolence—most emerge within the first few weeks and typically resolve with continued treatment. 1
• For duloxetine specifically, nausea can be reduced by starting at 30 mg daily for one week before increasing to 60 mg. 1, 5
• For venlafaxine, monitor blood pressure regularly due to risk of sustained hypertension. 1

Algorithm for Inadequate Response

• If no improvement after 8 weeks at therapeutic doses despite good adherence:
  • Switch to a different SSRI (e.g., sertraline to escitalopram or vice versa) 1
  • Switch to an SNRI (venlafaxine or duloxetine) 1
  • Add or intensify CBT if not already implemented 1

Critical Medications to Avoid

• Tricyclic antidepressants should be avoided due to unfavorable risk-benefit profile, particularly cardiac toxicity and high lethality in overdose. 1
• Beta blockers (atenolol, propranolol) are deprecated for GAD based on negative evidence. 4
• Antipsychotics (quetiapine) lack FDA approval and guideline endorsement for GAD and should not be used as first-line therapy. 1, 8

Discontinuation Strategy

• Taper gradually when stopping SSRIs/SNRIs to avoid discontinuation syndrome (dizziness, nausea, sensory disturbances, paresthesias), particularly with shorter half-life agents like paroxetine and venlafaxine. 1, 2
• Allow at least 14 days between discontinuing an MAOI and starting an SSRI/SNRI, and vice versa, to prevent serotonin syndrome. 2

Adjunctive Lifestyle Interventions

• Structured physical activity and regular cardiovascular exercise provide moderate to large reduction in anxiety symptoms. 1
• Avoid excessive caffeine and alcohol, as both exacerbate anxiety symptoms. 1
• Implement sleep hygiene education to address commonly co-occurring insomnia. 1
• Teach breathing techniques, progressive muscle relaxation, grounding strategies, and mindfulness as useful adjuncts. 1