What are some examples of Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs) for treating depression and anxiety in adult and geriatric patients?

Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs)

The SNRI class currently includes four medications marketed in the United States: duloxetine, venlafaxine (immediate and extended-release formulations), desvenlafaxine, and milnacipran. 1, 2

Available SNRI Medications

Duloxetine (Cymbalta)

• FDA-approved for multiple indications including major depressive disorder, generalized anxiety disorder (adults and pediatric patients ≥7 years), diabetic peripheral neuropathic pain, fibromyalgia, and chronic musculoskeletal pain 3, 4
• Has 10-fold selectivity for serotonin over norepinephrine reuptake 5
• Typical dosing: 30 mg once daily for one week, then 60 mg once daily (target dose for most conditions); maximum 120 mg/day 3
• Duloxetine is the only SNRI with FDA approval for treating any anxiety disorder in children and adolescents (generalized anxiety disorder in patients ≥7 years old) 3

Venlafaxine

• Available in immediate-release and extended-release formulations 2
• Has 30-fold selectivity for serotonin over norepinephrine reuptake 5
• Extended-release formulation allows once-daily dosing 2
• Associated with dose-dependent cardiovascular effects, principally hypertension, and is particularly associated with discontinuation symptoms 2, 5
• Associated with overdose fatalities 2

Desvenlafaxine

• FDA-approved for major depressive disorder with recommended doses of 50-100 mg/day 6
• Achieves steady-state plasma concentrations within 4-5 days 6
• Once-daily dosing with minimal impact on cytochrome P450 enzyme system 6
• Associated with overdose fatalities 2

Milnacipran

• Blocks serotonin and norepinephrine reuptake with equal affinity (1:1 ratio) 7, 5
• Evidence for analgesic efficacy in varied types of chronic pain, though less robust than duloxetine 1
• Better tolerated than venlafaxine and essentially devoid of cardiovascular toxicity 5

Mechanism of Action

SNRIs inhibit presynaptic reuptake of both norepinephrine and serotonin in the brain, which modulates central pain pathways and improves mood and anxiety symptoms 3, 8

Clinical Efficacy Considerations

Comparative Effectiveness

• SNRIs demonstrate comparable efficacy to SSRIs for anxiety disorders (NNT = 4.94 for SNRIs vs 4.70 for SSRIs) 2
• The double polarity of reuptake inhibition ensures effectiveness comparable to tricyclic antidepressants and potentially higher than SSRIs, especially in severe depression 8
• In contrast to SSRIs, which are generally ineffective in treating chronic pain, all SNRIs appear helpful in relieving chronic pain associated with and independent of depression 5

Evidence Strength by Agent

• Among SNRIs, evidence is strongest for duloxetine and less robust for milnacipran, venlafaxine, and desvenlafaxine 1
• Duloxetine often is considered first-line due to superior safety profile compared to other options 1

Safety and Tolerability Profile

Common Adverse Effects

• Approximately 63% of patients receiving SNRIs experience at least one adverse effect during treatment 1
• Common effects include nausea, dry mouth, headache, constipation, dizziness, decreased appetite, fatigue/somnolence, diaphoresis, abdominal discomfort, vomiting, diarrhea, tremor, insomnia, and weight loss 1, 2
• Nausea and vomiting are the most common reasons for discontinuation 1

Cardiovascular Monitoring

• SNRIs are associated with sustained hypertension, increased blood pressure, and increased pulse, requiring regular monitoring at every visit 9, 2
• Venlafaxine has dose-dependent cardiovascular effects, principally hypertension 5
• Duloxetine and milnacipran appear better tolerated and essentially devoid of cardiovascular toxicity 5

Bleeding Risk

• SNRIs increase bleeding risk, particularly when combined with NSAIDs, aspirin, warfarin, or other anticoagulants 2

Serotonin Syndrome Risk

• SNRIs can precipitate serotonin syndrome, a potentially life-threatening condition, especially with concomitant use of other serotonergic drugs (triptans, tricyclic antidepressants, fentanyl, tramadol, meperidine, methadone, lithium, tryptophan, buspirone, amphetamines, St. John's Wort) or MAOIs 7
• Symptoms include mental status changes, autonomic instability, neuromuscular symptoms, seizures, and gastrointestinal symptoms 7

Discontinuation Syndrome

• SNRIs require slow taper upon discontinuation—never stop abruptly, as venlafaxine is particularly associated with severe discontinuation symptoms 1, 2
• Dose tapering is advisable over at least 2-4 weeks to reduce risk of withdrawal syndrome, especially after treatment longer than 3 weeks 1, 3
• Discontinuation syndrome manifests primarily as adrenergic hyperactivity, dizziness, and anxiety 3

Special Population Considerations

Geriatric Patients

• Preferred agents for older patients with depression include duloxetine, venlafaxine, escitalopram, sertraline, mirtazapine, and bupropion 1
• Cautious dose escalation with small increments at intervals allowing adequate observation (usually at least one week at each dose level) is recommended 1
• Older adults have increased risk of adverse effects including cognitive impairment, falls, and drug-drug interactions related to polypharmacy 1

Pediatric Patients

• Duloxetine is FDA-approved for generalized anxiety disorder in pediatric patients ≥7 years old 3
• SNRIs significantly improve clinician-reported primary anxiety symptoms compared to placebo in patients ages 6-18 years (high strength of evidence) 2

Critical Prescribing Pitfalls to Avoid

• Never combine SNRIs with MAOIs due to contraindication for serotonin syndrome 7
• Never discontinue abruptly—always taper gradually to prevent severe withdrawal symptoms 2
• Monitor blood pressure and pulse regularly, especially during initiation and dose escalation 9, 2
• Educate patients specifically about serotonin syndrome symptoms and instruct them to seek immediate medical attention if symptoms develop 9
• Exercise caution when combining with anticoagulants or NSAIDs due to increased bleeding risk 2