What alternative medications can a patient with anxiety take if they cannot take a selective serotonin reuptake inhibitor (SSRI)?

Alternative Medications for Anxiety When SSRIs Cannot Be Used

For patients who cannot take SSRIs, serotonin-norepinephrine reuptake inhibitors (SNRIs) such as venlafaxine (75-225 mg/day) or duloxetine (60-120 mg/day) are the preferred first-line pharmacological alternatives, with buspirone (15-60 mg/day) as a viable non-sedating second option. 1

Primary Pharmacological Alternatives

SNRIs as First-Line Substitutes

• Venlafaxine extended-release (75-225 mg/day) demonstrates statistically significantly better response and remission rates than SSRIs in treatment-resistant cases and is effective for generalized anxiety disorder, panic disorder, and social anxiety disorder. 2, 1
• Start venlafaxine at 37.5-75 mg daily and titrate gradually to minimize side effects, with blood pressure monitoring required due to risk of sustained hypertension. 2, 1
• Duloxetine (60-120 mg/day) has demonstrated efficacy in GAD and provides 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

Buspirone as Non-Sedating Alternative

• Buspirone is recommended as a first-line treatment for generalized anxiety disorder when SSRIs cannot be used, with an initial dose of 15 mg daily (7.5 mg twice daily), increasing by 5 mg every 2-3 days as needed, up to a maximum of 60 mg daily. 3, 4
• Buspirone requires 2-4 weeks for onset of anxiolytic effects and is most appropriate for patients with chronic generalized anxiety who do not require immediate symptom relief. 5, 6
• This medication lacks dependency potential, sedation, and withdrawal symptoms that characterize benzodiazepines, making it safer for long-term use. 5, 6
• Buspirone should be taken consistently either always with food or always without food, as bioavailability increases when taken with meals. 3

Second-Line Pharmacological Options

Pregabalin/Gabapentin

• These medications can be considered when first-line treatments (SNRIs or buspirone) are ineffective or not tolerated, and have shown efficacy in GAD, particularly for patients with comorbid pain conditions. 1

Tricyclic Antidepressants (Use with Caution)

• Secondary amine TCAs such as desipramine or nortriptyline may be beneficial due to lower anticholinergic effects compared to tertiary amines. 2
• Start at low doses (e.g., 10 mg at bedtime) and titrate gradually to minimize side effects including dry mouth, sedation, and constipation. 2
• TCAs should generally be avoided due to unfavorable risk-benefit profile, particularly cardiac toxicity, and are reserved for cases where multiple first-line agents have failed. 1

Medications to Avoid or Use Only Short-Term

Benzodiazepines

• Benzodiazepines should be reserved for short-term use only (days to weeks, not months) due to risks of dependence, tolerance, withdrawal, and cognitive impairment. 1, 7
• If benzodiazepines must be used, slower-onset, longer-acting agents are preferred over alprazolam. 7
• The Canadian guideline explicitly deprecates beta-blockers (atenolol, propranolol) for social anxiety disorder based on negative evidence. 1

Essential Non-Pharmacological Treatment

Cognitive Behavioral Therapy

• CBT should be offered to all patients with anxiety disorders, as it demonstrates efficacy comparable to or exceeding pharmacotherapy alone, with large effect sizes (Hedges g = 1.01 for GAD). 1
• Individual CBT is prioritized over group therapy due to superior clinical and cost-effectiveness. 1
• A structured duration of 12-20 CBT sessions is recommended to achieve significant symptomatic and functional improvement. 1
• Combining medication (SNRI or buspirone) with CBT provides superior outcomes compared to either treatment alone for moderate to severe anxiety. 1

Treatment Timeline and Monitoring

• Allow 6-8 weeks at therapeutic doses before declaring treatment failure with SNRIs or buspirone. 2, 1
• Assess response using standardized anxiety rating scales (GAD-7 or HAM-A) every 2-4 weeks initially, then every 3 months once stabilized. 1
• Continue effective medication for a minimum of 9-12 months after achieving remission to prevent relapse. 1
• Monitor for common SNRI side effects including nausea, sexual dysfunction, headache, insomnia, and blood pressure elevation with venlafaxine. 1

Critical Pitfalls to Avoid

• Do not use bupropion for anxiety disorders, as it is activating and can exacerbate anxiety symptoms, agitation, and nervousness. 1
• Do not combine buspirone with MAOIs; at least 14 days must elapse between discontinuation of an MAOI and initiation of buspirone. 3
• Do not expect immediate anxiety relief with buspirone; patients must understand the 2-4 week onset period to prevent premature discontinuation. 5
• Do not prescribe benzodiazepines for chronic anxiety management due to dependency risk and lack of evidence for long-term efficacy. 1, 7