What are the best first‑line medications for panic disorder and other anxiety disorders, including recommended agents, dosing, and safety considerations?

Best Medications for Panic and Anxiety Disorders

Selective serotonin reuptake inhibitors (SSRIs)—specifically escitalopram or sertraline—are the first-line pharmacological treatments for panic disorder and most anxiety disorders, with serotonin-norepinephrine reuptake inhibitors (SNRIs) such as venlafaxine or duloxetine serving as effective alternatives when SSRIs fail or are not tolerated. 1, 2

First-Line Pharmacotherapy: SSRIs

Preferred Agents and Rationale

• Escitalopram and sertraline are the top-tier first-line SSRIs because they have the lowest potential for drug-drug interactions, the smallest discontinuation-symptom burden, and favorable safety profiles compared with other SSRIs. 2
• All SSRIs as a class demonstrate robust efficacy for anxiety disorders, with moderate to high strength of evidence showing improvement in primary anxiety symptoms, treatment response rates, and remission. 1, 2
• The number needed to treat (NNT) for SSRIs in anxiety disorders is approximately 4.7, meaning roughly 1 in 5 patients will respond to SSRIs who would not have responded to placebo. 2

Dosing Recommendations

For Sertraline:

• Start at 25–50 mg daily to minimize initial anxiety or agitation that can occur with SSRIs. 2
• Titrate by 25–50 mg increments every 1–2 weeks as tolerated. 2
• Target therapeutic dose: 50–200 mg/day. 2

For Escitalopram:

• Start at 5–10 mg daily. 2
• Titrate by 5–10 mg increments every 1–2 weeks. 2
• Target therapeutic dose: 10–20 mg/day. 2

For Fluoxetine:

• Start at 5–10 mg daily and increase by 5–10 mg increments every 1–2 weeks. 2
• Target therapeutic dose: 20–40 mg daily by weeks 4–6. 2
• Fluoxetine has a longer half-life that may benefit patients who occasionally miss doses. 2

Expected Timeline for Response

• Statistically significant improvement may begin by week 2. 1, 2
• Clinically significant improvement is expected by week 6. 1, 2
• Maximal therapeutic benefit is achieved by week 12 or later. 1, 2
• This logarithmic response pattern supports slow up-titration to avoid exceeding the optimal dose. 1, 2

Common Side Effects

Most adverse effects emerge within the first few weeks and typically resolve with continued treatment: 1, 2

• Nausea, diarrhea, dry mouth, heartburn
• Headache, dizziness, somnolence or insomnia
• Sexual dysfunction
• Nervousness, tremor, vivid dreams
• Changes in appetite, weight fluctuations

Critical Safety Warning

• All SSRIs carry a boxed warning for suicidal thinking and behavior through age 24 years, with pooled absolute rates of 1% versus 0.2% for placebo. 1
• Close monitoring is essential, especially in the first months of treatment and following dose adjustments. 1, 2
• The number needed to harm (NNH) is 143. 2

Second-Tier SSRIs

Paroxetine and fluvoxamine are equally effective but recommended as second-tier agents due to: 2

• Higher rates of discontinuation symptoms
• Greater potential for drug-drug interactions
• Paroxetine has significant anticholinergic properties and potentially increased suicidal thinking compared to other SSRIs. 2

Second-Line Pharmacotherapy: SNRIs

When to Consider SNRIs

Switch to an SNRI after 8–12 weeks at therapeutic SSRI doses without adequate response. 2

Venlafaxine Extended-Release

• Dosing: Start at 75 mg daily, titrate to 75–225 mg/day over 4–6 weeks. 2
• Effective for generalized anxiety disorder, social anxiety disorder, and panic disorder with NNT comparable to SSRIs (4.94). 2, 3
• Requires blood pressure monitoring due to dose-dependent risk of sustained hypertension. 2
• Higher risk of discontinuation syndrome; taper gradually over 10–14 days or longer when stopping. 2

Duloxetine

• Dosing: Start at 30 mg daily for 1 week, then increase to 60 mg daily. 2, 4
• Target dose: 60–120 mg/day. 2, 4
• Additional benefits for patients with comorbid pain conditions. 2
• Common side effects include nausea (can be reduced by starting at 30 mg for one week). 2

Cognitive-Behavioral Therapy Integration

Combining an SSRI or SNRI with individual cognitive-behavioral therapy (CBT) yields superior outcomes compared with either treatment alone, supported by moderate-to-high strength evidence. 2, 5

CBT Specifications

• Individual CBT is preferred over group therapy due to superior clinical effectiveness and cost-effectiveness. 2
• Recommended duration: 12–20 sessions over 3–4 months for significant symptomatic and functional improvement. 2
• CBT should include: education on anxiety, cognitive restructuring, relaxation techniques, and gradual exposure when appropriate. 2
• If face-to-face CBT is unavailable, self-help CBT with professional support is a viable alternative. 2

Medications to Avoid

Benzodiazepines

• Should be limited to short-term (days to a few weeks) adjunctive use only due to high risk of dependence, tolerance, cognitive impairment, and withdrawal syndromes. 2, 6
• Not recommended as first-line or long-term therapy for anxiety or panic disorders. 2
• Common side effects include drowsiness, light-headedness, confusion, and increased fall risk. 6

Beta-Blockers

• Beta-blockers (atenolol, propranolol) are deprecated by Canadian guidelines for generalized anxiety disorder and social anxiety disorder based on negative evidence. 2

Tricyclic Antidepressants

• Should be avoided due to unfavorable risk-benefit profile, particularly cardiac toxicity, marked anticholinergic effects, and increased risk of cardiac arrest. 2

Treatment Duration and Maintenance

• Continue effective medication for a minimum of 9–12 months after achieving remission to prevent relapse. 2
• For recurrent anxiety, longer-term or indefinite treatment may be beneficial. 7
• Reassess monthly until symptoms stabilize, then every 3 months. 2

Management of Treatment Resistance

If no improvement after 8–12 weeks at therapeutic doses despite good adherence: 2

1. Switch to a different SSRI (e.g., sertraline to escitalopram or vice versa)
2. Switch to an SNRI (venlafaxine or duloxetine)
3. Add individual CBT if not already implemented
4. Consider augmentation with pregabalin or gabapentin for patients with comorbid pain conditions 2

Special Populations

Children and Adolescents (6–18 years)

• SSRIs are recommended for social anxiety, generalized anxiety, separation anxiety, and panic disorders in this age group. 1
• Dosing requires adjustment for age and weight, with slower titration than adults. 1

Elderly Patients

• Sertraline and escitalopram are preferred due to favorable safety profiles and low drug interaction potential. 7
• Start at lower doses (approximately 50% of standard adult starting doses) and titrate gradually. 7
• Escitalopram maximum dose is 20 mg daily in patients >60 years to avoid QT prolongation. 7
• Avoid paroxetine and fluoxetine in older adults due to higher rates of adverse effects. 7

Common Pitfalls to Avoid

• Do not abandon treatment prematurely—full response may take 12+ weeks. 2
• Do not escalate doses too quickly—allow 1–2 weeks between increases to assess tolerability. 2
• Do not discontinue SSRIs abruptly—taper gradually to avoid discontinuation syndrome (dizziness, paresthesias, anxiety, irritability). 2
• Do not use benzodiazepines as monotherapy or for long-term management. 2
• Approximately 50% of patients do not achieve full remission with first-line pharmacotherapy alone, underscoring the need for combined treatment with CBT. 2