Non-Sedative Anti-Anxiety Medications
SSRIs (escitalopram or sertraline) and SNRIs (duloxetine or venlafaxine) are the recommended non-sedative first-line treatments for anxiety disorders, with SSRIs preferred due to their established efficacy, favorable safety profiles, and minimal sedation. 1, 2
First-Line Non-Sedative Options
SSRIs (Preferred)
- Escitalopram and sertraline are top-tier first-line agents due to their superior efficacy, favorable side effect profiles, and lower risk of discontinuation symptoms compared to other SSRIs 2
- Start escitalopram at 5-10 mg daily and titrate by 5-10 mg increments every 1-2 weeks, targeting 10-20 mg/day 2
- Start sertraline at 25-50 mg daily and titrate by 25-50 mg increments every 1-2 weeks, targeting 50-200 mg/day 2
- Fluoxetine (5-10 mg initially, targeting 20-40 mg daily) offers the advantage of a longer half-life, which may benefit patients who occasionally miss doses 2
- Paroxetine and fluvoxamine are equally effective but carry higher risks of discontinuation symptoms and should be reserved for when first-tier SSRIs fail 1, 2
SNRIs (Alternative First-Line)
- Venlafaxine extended-release (75-225 mg/day) is effective for generalized anxiety disorder, social anxiety disorder, and panic disorder but requires blood pressure monitoring due to risk of sustained hypertension 1, 2
- Duloxetine (60-120 mg/day) has demonstrated efficacy in GAD and provides additional benefits for patients with comorbid pain conditions 2
- Start duloxetine at 30 mg daily for one week to reduce nausea, then increase to 60 mg 2
Expected Response Timeline
- Statistically significant improvement may begin by week 2, with clinically significant improvement expected by week 6, and maximal therapeutic benefit achieved by week 12 or later 2
- Do not abandon treatment prematurely—full response may take 12+ weeks 2
- Most adverse effects (nausea, headache, insomnia) emerge within the first few weeks and typically resolve with continued treatment 2
Second-Line Non-Sedative Options (When SSRIs/SNRIs Fail)
Pregabalin and Gabapentin
- Pregabalin has demonstrated efficacy as a second-line treatment for anxiety disorders, particularly for patients with comorbid pain conditions 3, 2
- Gabapentin is recommended as a second-line option for patients with comorbid pain conditions 3
- These calcium modulators are non-sedating alternatives when first-line treatments are ineffective or not tolerated 4
Medications to Avoid
- Benzodiazepines (alprazolam, clonazepam) are NOT recommended as non-sedative options due to their inherent sedative properties and addiction potential 3, 4
- Beta blockers (atenolol, propranolol) have negative evidence for social anxiety disorder and should be avoided 2
- Tricyclic antidepressants should be avoided due to their unfavorable risk-benefit profile, particularly cardiac toxicity 2
- Quetiapine has negative evidence for social anxiety disorder 3
Critical Treatment Algorithm
Step 1: Initiate escitalopram or sertraline at low doses, titrating gradually over 1-2 weeks 2
Step 2: If inadequate response after 8-12 weeks at therapeutic doses, switch to a different SSRI or try an SNRI (duloxetine or venlafaxine) 2
Step 3: If two SSRI/SNRI trials fail, consider pregabalin or gabapentin as second-line agents 3, 2
Step 4: Combine medication with individual cognitive behavioral therapy (CBT) for optimal outcomes, as combination therapy often yields better results than either approach alone 3, 2
Important Monitoring Considerations
- Assess response using standardized anxiety rating scales (e.g., HAM-A) 2
- Monitor for common side effects: nausea, sexual dysfunction, headache, insomnia, dry mouth, diarrhea 2
- Monitor closely for suicidal thinking and behavior, especially in the first months and following dose adjustments 2
- For venlafaxine, monitor blood pressure increases 2
- Allow 1-2 weeks between dose increases to assess tolerability and avoid overshooting the therapeutic window 2