What is the recommended treatment for Generalized Anxiety Disorder (GAD)?

Treatment of Generalized Anxiety Disorder (GAD)

Start with an SSRI (escitalopram 10-20 mg/day or sertraline 50-200 mg/day) or SNRI (duloxetine 60-120 mg/day or venlafaxine 75-225 mg/day) as first-line pharmacotherapy, combined with cognitive behavioral therapy (CBT) when feasible for optimal outcomes. 1

First-Line Pharmacological Treatment

SSRIs as Primary Option

• SSRIs demonstrate high-quality evidence for efficacy in GAD, with improvement in primary anxiety symptoms, treatment response, and remission rates (moderate to high strength of evidence). 2, 1
• Escitalopram (10-20 mg/day) and sertraline (50-200 mg/day) are the preferred SSRIs due to their established efficacy, favorable side effect profiles, and lower risk of discontinuation symptoms compared to other SSRIs. 1
• Start with low doses (sertraline 25-50 mg daily or escitalopram 5-10 mg daily) to minimize initial anxiety/agitation that can occur with SSRIs. 1
• Titrate sertraline by 25-50 mg increments every 1-2 weeks as tolerated; escitalopram by 5-10 mg increments. 1

SNRIs as Alternative First-Line

• Duloxetine (60-120 mg/day) and venlafaxine extended-release (75-225 mg/day) are equally effective first-line alternatives, particularly beneficial for patients with comorbid pain conditions. 1
• Venlafaxine requires blood pressure monitoring due to risk of sustained hypertension. 1, 3
• Start duloxetine at 30 mg daily for one week to reduce nausea, then increase to 60 mg. 1

Expected Timeline and Monitoring

• Response follows a logarithmic pattern: statistically significant improvement begins at week 2, clinically significant improvement expected at week 6, and maximal therapeutic benefit achieved at week 12 or later. 1
• Assess response using standardized anxiety rating scales (e.g., HAM-A) at regular intervals. 1
• Most adverse effects (nausea, headache, insomnia, sexual dysfunction, dizziness) emerge within the first few weeks and typically resolve with continued treatment. 1

Combination Treatment Approach

Combining medication with CBT provides superior outcomes compared to either treatment alone (moderate strength of evidence). 2, 1

CBT Components

• Individual CBT is prioritized over group therapy due to superior clinical and cost-effectiveness (large effect size for GAD: Hedges g = 1.01). 1
• CBT should include: education on anxiety, cognitive restructuring to challenge distortions, relaxation techniques, and gradual exposure when appropriate. 1
• A structured duration of 12-20 CBT sessions is recommended to achieve significant symptomatic and functional improvement. 1

Second-Line and Adjunctive Options

When First-Line Treatment Fails

• If inadequate response after 8-12 weeks at therapeutic doses, switch to a different SSRI or SNRI (e.g., sertraline to escitalopram or vice versa). 1
• Pregabalin/gabapentin can be considered when first-line treatments are ineffective or not tolerated, particularly for patients with comorbid pain conditions. 1

Adjunctive Non-Pharmacological Interventions

• Structured physical activity and exercise provide moderate to large reduction in anxiety symptoms. 1
• Breathing techniques, progressive muscle relaxation, grounding strategies, visualization, and mindfulness are useful adjunctive strategies. 1
• Provide psychoeducation to family members about anxiety symptoms and treatment. 1

Critical Warnings and Monitoring

Suicidality Risk

• All SSRIs carry a boxed warning for suicidal thinking and behavior, with pooled absolute rates of 1% versus 0.2% for placebo (number needed to harm = 143). 1
• Close monitoring is essential, especially in the first months and following dose adjustments. 1

Common Side Effects to Monitor

• Nausea, sexual dysfunction, headache, insomnia, dry mouth, diarrhea, heartburn, somnolence, dizziness, and vivid dreams. 1
• For venlafaxine: monitor blood pressure increases and weight loss. 3
• For duloxetine: nausea is common but can be reduced by starting at 30 mg daily for one week. 1

Discontinuation Considerations

• Discontinue medication gradually to avoid withdrawal symptoms, particularly with shorter half-life SSRIs like paroxetine and sertraline. 2, 1
• Paroxetine has the highest risk of discontinuation syndrome and should be reserved for when first-tier SSRIs fail. 1
• Decrease daily dosage by no more than 0.5 mg every 3 days when discontinuing; some patients may require even slower reduction. 4

Medications to Avoid or Use Cautiously

Benzodiazepines

• Benzodiazepines (e.g., alprazolam) should be reserved for short-term use only due to risks of dependence, tolerance, and withdrawal. 1
• While alprazolam is FDA-approved for GAD, it lacks antidepressant efficacy important for addressing comorbid depression experienced by many patients. 4, 5
• If used, initiate with 0.25-0.5 mg three times daily, with maximum daily dose of 4 mg in divided doses. 4

Tricyclic Antidepressants

• Tricyclic antidepressants should be avoided due to their unfavorable risk-benefit profile, particularly cardiac toxicity. 1

Treatment Duration and Long-Term Management

• GAD is a chronic illness requiring long-term treatment; remission is attainable but can take several months. 6
• Continue treatment for at least 6-12 months after symptom remission to prevent relapse. 2
• Consider tapering medication if anxiety symptoms are under control and primary environmental sources of anxiety are no longer present. 2
• Stopping medication increases the risk of relapse within the first year of initiating treatment. 6

Common Pitfalls to Avoid

• Do not escalate doses too quickly; allow 1-2 weeks between increases for shorter half-life SSRIs to assess tolerability and avoid overshooting the therapeutic window. 1
• Do not abandon treatment prematurely; full response may take 12+ weeks. 1
• Do not use benzodiazepines as first-line long-term treatment despite their rapid onset, due to dependence risk and lack of antidepressant efficacy. 1, 5
• Do not ignore comorbid depression; antidepressants (SSRIs/SNRIs) are more likely to succeed than benzodiazepines in patients with significant depression. 6