SNRI as Adjunct Therapy for Anxiety
SNRIs can be offered as monotherapy for anxiety disorders including generalized anxiety disorder, social anxiety disorder, separation anxiety disorder, and panic disorder, but the evidence does not specifically support their use as adjunct therapy—they are effective as standalone first-line pharmacological treatments. 1
Primary Role: Monotherapy, Not Adjunct
The available evidence addresses SNRIs as primary pharmacological treatment rather than adjunctive therapy:
- SNRIs as a class significantly improve clinician-reported primary anxiety symptoms compared to placebo (high strength of evidence), based on 4 RCTs including 911 patients ages 6-18 years 1
- SNRIs demonstrate comparable efficacy to SSRIs for anxiety disorders, with similar response rates (NNT = 4.94 for SNRIs vs 4.70 for SSRIs) and comparable dropout rates to placebo 1
- First-line pharmacotherapy status: Both SSRIs and SNRIs are considered first-line pharmacological treatments for generalized anxiety disorder, social anxiety disorder, and panic disorder, with small to medium effect sizes compared to placebo 2
Available SNRI Medications
The SNRI class includes four medications currently marketed in the United States 1:
- Venlafaxine (immediate and extended release formulations)
- Desvenlafaxine
- Duloxetine (the only SNRI with FDA indication for generalized anxiety disorder in children/adolescents ≥7 years old) 1, 3
- Levomilnacipran
Note: Atomoxetine is NOT recommended for anxiety as a primary disorder, despite being included in some reviews 1
Mechanism Supporting Efficacy
SNRIs inhibit presynaptic reuptake of both norepinephrine and serotonin, which paradoxically reduces anxiety despite norepinephrine's association with the "fight or flight" stress response, likely through complex neurotransmitter interactions 1
- Noradrenergic neurons modulate alertness, arousal, attentiveness, and vigilance 1
- Evidence supports disturbed noradrenergic neurotransmission contributing to anxiety symptoms, including increased MHPG metabolite levels and noradrenaline hypersecretion 4
- Dual action on both serotonin and norepinephrine systems may provide advantages over selective agents in certain anxiety disorders 5, 4
Dosing Considerations
Extended-release formulations allow once-daily dosing 1:
- Venlafaxine extended release, desvenlafaxine, and duloxetine have sufficiently long elimination half-lives for single daily dosing
- Venlafaxine immediate release requires twice- or thrice-daily dosing due to short elimination half-life
- Duloxetine delayed-release capsules must be swallowed whole—do not chew, crush, open, or mix with food/liquids 3
Critical Safety Considerations
Black Box Warning: Suicidality
SNRIs carry increased risk of suicidal thoughts or actions in children, teenagers, and young adults within the first few months of treatment or when dose is changed 3
Cardiovascular Monitoring Required
- Monitor blood pressure and pulse regularly—SNRIs are associated with sustained hypertension, increased blood pressure, and increased pulse 1
- Venlafaxine demonstrates dose-dependent cardiovascular effects, principally hypertension, and appears least well-tolerated within the SNRI class 6
Orthostatic Hypotension and Falls
SNRIs cause orthostatic hypotension, falls, and syncope, particularly in the first week of therapy or after dose increases 3:
- Risk increases with age, concomitant antihypertensives, potent CYP1A2 inhibitors, and doses >60 mg daily
- Falls with serious consequences including fractures and hospitalizations have been reported
- Consider dose reduction or discontinuation if symptomatic orthostatic hypotension occurs
Hepatotoxicity
Duloxetine should not be prescribed to patients with substantial alcohol use or chronic liver disease 3:
- Duloxetine associated with hepatic failure, cholestatic jaundice, and transaminase elevations
- Discontinue immediately if jaundice or clinically significant liver dysfunction develops
- Severe skin reactions (Stevens-Johnson syndrome, erythema multiforme) can occur with duloxetine 1
Serotonin Syndrome
Concomitant use with MAOIs is contraindicated—do not use within 14 days of MAOI discontinuation or within 5 days after stopping duloxetine 3
- Risk increased with other serotonergic drugs (triptans, tramadol, fentanyl, lithium, SSRIs, tricyclics, St. John's Wort, tryptophan, amphetamines)
- Monitor for mental status changes, autonomic instability, neuromuscular symptoms, and GI symptoms 3
Bleeding Risk
SNRIs increase bleeding risk, particularly when combined with NSAIDs, aspirin, warfarin, or other anticoagulants 3:
- Higher incidence of postpartum hemorrhage reported
- Events range from ecchymoses to life-threatening hemorrhages
Common Adverse Effects
Compared to placebo, SNRIs are associated with increased fatigue/somnolence (moderate strength of evidence) 1
Additional common effects include 1:
- Diaphoresis, dry mouth
- Abdominal discomfort, nausea, vomiting, diarrhea
- Dizziness, headache, tremor
- Insomnia, decreased appetite, weight loss
Discontinuation Syndrome
SNRIs require slow taper upon discontinuation—never stop abruptly 1, 3:
- Venlafaxine particularly associated with discontinuation symptoms
- Both venlafaxine and desvenlafaxine associated with overdose fatalities 1
Clinical Pitfalls to Avoid
Do not use SNRIs as adjunct when evidence supports monotherapy: The guideline evidence addresses SNRIs as standalone treatment, not augmentation strategy [1-1]
Do not assume class equivalence for safety: Venlafaxine carries greater suicide risk and cardiovascular toxicity compared to other SNRIs 1, 6
Do not overlook drug interactions: Duloxetine interacts with CYP1A2 and CYP2D6 substrates; venlafaxine has least CYP450 effects 1
Do not ignore diabetes management: SNRIs make blood sugar control harder in diabetic patients 3
Do not use in patients with uncontrolled narrow-angle glaucoma 3